Animation Supported Consent Before Elective Laparoscopic Cholecystectomy.

BACKGROUND: Patient understanding of surgical procedures is often incomplete at the time they are performed, invalidating consent, and exposing healthcare providers to complaints and claims of failure to inform. Remote consultations, language barriers and patient factors can hinder an effective consent pathway. New approaches are needed to support communication and shared decision-making. METHODS: Multi-language digital animations explaining laparoscopic cholecystectomy were introduced at The Royal London Hospital for patients who attended for elective surgery ( www.explainmyprocedure.com/lapchole ). Patients completed questionnaires on the day of their procedure both before and after introduction of the animations. We assessed patient-reported understanding of the procedure, its intended benefits, the possible risks, and alternatives to treatment in 72 consecutive patients, 37 before (no animation group) and after 35 after introducing the animations into the consent pathway (animation group). Patient understanding in the two groups was compared. RESULTS: The two groups were well matched in respect of age, sex and whether English was their first spoken language. The proportions of patients who reported they completely understood the procedure, its benefits, risks, and alternatives in the no animation group were 54, 57, 38 and 24% and in the animation group, 91, 91, 74 and 77%, respectively; p < 0.01 for each comparison. CONCLUSION: The integration of multi-language laparoscopic cholecystectomy video animations into the patient consent pathway was associated with substantial improvement in reported understanding of the procedure, benefits, risks, and alternatives to treatment. This approach can be applied across all surgical disciplines in a standardised manner in an era of accelerated elective work and remote consultations.

PD-L1 Testing in Urothelial Carcinoma: Analysis of a Series of 1401 Cases Using Both the 22C3 and SP142 Assays.

Immune checkpoint blockade (ICB) drugs are a novel, effective treatment for advanced urothelial carcinoma. Worldwide, several different ICB drugs are approved, each developed and clinically validated with a specific PD-L1 compound diagnostic assay. As a result, PD-L1 testing workflows in routine practice are complex: requiring multiple assays across two platforms, with each assay having a different method of interpretation. Our service tested 1,401 urothelial carcinoma cases for PD-L1 expression, using both the 22C3 PharmDx assay (required prior to Pembrolizumab therapy) and SP142 assay (required prior to Atezolizumab therapy). Of the 1,401 cases tested, 621 cases (44%) were tested with both the 22C3 PharmDx and SP142 assays, 492 cases (35%) with 22C3 PharmDx only, and 288 cases (21%) with SP142 only. Each assay was used and interpreted according to the manufacturer's guidelines. The rate of positivity we observed was 26% with the 22C3 assay and 31% with the SP142 assay, similar to the pre-licensing studies for both drugs. The discrepancy observed between the assays was 11%, which reinforces the requirement for utilisation of the correct assay for each agent, and limits potential cross-utility of assays. This aspect must be considered when setting up a PD-L1 testing strategy in laboratories where both Pembrolizumab and Atezolizumab are available for the treatment of urothelial carcinoma but also has broader implications for testing of other cancers where multiple ICB drugs and their respective assays are approved.

Clonal Transitions and Phenotypic Evolution in Barrett's Esophagus.

BACKGROUND & AIMS: Barrett's esophagus (BE) is a risk factor for esophageal adenocarcinoma but our understanding of how it evolves is poorly understood. We investigated BE gland phenotype distribution, the clonal nature of phenotypic change, and how phenotypic diversity plays a role in progression. METHODS: Using immunohistochemistry and histology, we analyzed the distribution and the diversity of gland phenotype between and within biopsy specimens from patients with nondysplastic BE and those who had progressed to dysplasia or had developed postesophagectomy BE. Clonal relationships were determined by the presence of shared mutations between distinct gland types using laser capture microdissection sequencing of the mitochondrial genome. RESULTS: We identified 5 different gland phenotypes in a cohort of 51 nondysplastic patients where biopsy specimens were taken at the same anatomic site (1.0-2.0 cm superior to the gastroesophageal junction. Here, we observed the same number of glands with 1 and 2 phenotypes, but 3 phenotypes were rare. We showed a common ancestor between parietal cell-containing, mature gastric (oxyntocardiac) and goblet cell-containing, intestinal (specialized) gland phenotypes. Similarly, we have shown a clonal relationship between cardiac-type glands and specialized and mature intestinal glands. Using the Shannon diversity index as a marker of gland diversity, we observed significantly increased phenotypic diversity in patients with BE adjacent to dysplasia and predysplasia compared to nondysplastic BE and postesophagectomy BE, suggesting that diversity develops over time. CONCLUSIONS: We showed that the range of BE phenotypes represents an evolutionary process and that changes in gland diversity may play a role in progression. Furthermore, we showed a common ancestry between gastric and intestinal-type glands in BE.

Acute haemorrhage rate in 28,000 Out-of-Hours CT heads.

OBJECTIVES: The aim of this paper is to assess the acute haemorrhage rate in patients who had CT head investigation out-of-hours with and without trauma and compare the rates of haemorrhage between warfarin and DOACs, at a busy teritary teaching hospital. METHODS: All CT heads performed between January 2008 and December 2019 were identified from the radiology information system (RIS) at Sheffield Teaching Hospitals (STH), with the requesting information being available from January 2015. The clinical information was assessed for the mention of trauma or anticoagulation, and the reports were categorised into acute and non-acute findings. RESULTS: Between 2008 and 2019 the number of scans increased by 63%, with scans performed out of hours increasing by 278%. Between 2015 and 2019, the incidence of acute ICH was similar over the 5-year period, averaging at 6.9% and ranging from 6.1 to 7.6%. The rate of detection of acute haemorrhage following trauma was greater in those not anticoagulated (6.8%), compared with patients on anticoagulants such as warfarin (5.2%) or DOACs (2.8%). CONCLUSIONS: Over 12 years, there has been a significant increase in the number of CT heads performed at STH. The rate of ICH has remained steady over the last 5 years indicating a justified increase in imaging demand. However, the incidence of ICH in patients prescribed DOACs is lower than the general population and those on warfarin. ADVANCES IN KNOWLEDGE: This finding in a large centre should prompt discussion of the risk of bleeding with DOACs in relation to CT head imaging guidelines.

The Clinicopathological and Molecular Associations of PD-L1 Expression in Non-small Cell Lung Cancer: Analysis of a Series of 10,005 Cases Tested with the 22C3 Assay.

PD-L1 expression testing is mandatory prior to pembrolizumab prescription in non-small cell lung cancer. Our service offers PD-L1 testing using the PD-L1 IHC 22C3 pharmDx assay, in parallel with EGFR, ALK, ROS1 and (in some cases) KRAS testing. We correlate PD-L1 expression in 10,005 tumours with patient age and sex, with tumour histological subtypes, with the sampling modality and type of tissue, and with the presence of other molecular alterations. PD-L1 expression testing was performed using the aforementioned assay; tumour proportion scores (TPS) of 1 and 50% were taken as cut-offs for low and high positivity, respectively. EGFR testing was performed using the cobas® EGFR Mutation Test v2. ALK testing was performed using the VENTANA ALK (D5F3) CDx Assay. KRAS testing was performed using pyrosequencing. TPS <1% was seen in 44.4% of tumours, 1-49% in 25.0% and ≥ 50% in 30.6%. We identified no significant relationship with age. Female patients were slightly more likely to express PD-L1. Poorly-differentiated tumour histology and ALK translocation were significantly associated with PD-L1 expression. Rare EGFR mutations tended to be associated with PD-L1 expression. Pleural and nodal metastases were more likely to express PD-L1 than primary tumours, but biopsy and cytological specimens did not show different PD-L1 expression rates. Our data show that the means of acquiring a tumour sample (biopsy versus cytology) does not have a significant impact on PD-L1 expression. However, we found that certain metastatic sites were associated with significantly higher expression rates, which has substantial implications for selection of tissue for testing.

A CEP104-CSPP1 Complex Is Required for Formation of Primary Cilia Competent in Hedgehog Signaling.

CEP104 is an evolutionarily conserved centrosomal and ciliary tip protein. CEP104 loss-of-function mutations are reported in patients with Joubert syndrome, but their function in the etiology of ciliopathies is poorly understood. Here, we show that cep104 silencing in zebrafish causes cilia-related manifestations: shortened cilia in Kupffer's vesicle, heart laterality, and cranial nerve development defects. We show that another Joubert syndrome-associated cilia tip protein, CSPP1, interacts with CEP104 at microtubules for the regulation of axoneme length. We demonstrate in human telomerase reverse transcriptase-immortalized retinal pigmented epithelium (hTERT-RPE1) cells that ciliary translocation of Smoothened in response to Hedgehog pathway stimulation is both CEP104 and CSPP1 dependent. However, CEP104 is not required for the ciliary recruitment of CSPP1, indicating that an intra-ciliary CEP104-CSPP1 complex controls axoneme length and Hedgehog signaling competence. Our in vivo and in vitro analyses of CEP104 define its interaction with CSPP1 as a requirement for the formation of Hedgehog signaling-competent cilia, defects that underlie Joubert syndrome.

Large-Scale EGFR Mutation Testing in Clinical Practice: Analysis of a Series of 18,920 Non-Small Cell Lung Cancer Cases.

We make use of a very large dataset of non-small cell lung cancer specimens to examine the molecular epidemiology of EGFR mutations, particularly with respect to rare and compound mutations, and to non-adenocarcinoma histological subtypes. We also demonstrate the feasibility of large-scale EGFR mutation screening using the full range of specimens encountered in routine practice. We retrospectively reviewed 18,920 unselected EGFR mutation results from our centre between July 2009 and October 2016, using Qiagen's therascreen EGFR RGQ PCR Kit. Mutation rates were correlated with patient demographics and tumour histology. Our testing success rate was 93.9%, with similar success rates using histological and cytological specimens. Rare, potentially-targetable mutations accounted for 9.5% of all mutations detected. We identified a 2.5% mutation rate in tumours diagnosed as squamous cell carcinomas. There was a trend towards increasing EGFR mutation rates with increasing age, and while Del19 was the commonest mutation in the young, L858R predominated in the elderly. We found that EGFR mutation heterogeneity is rare within tumours and between primary and metastatic deposits. Our data demonstrate that large-scale, reflex EGFR mutation testing is feasible and affordable in the context of a publicly-funded health system. Furthermore, we have shown that the use of techniques sensitive only to classical mutations and selection of patients on the grounds of age, sex and histology denies patients access to potentially beneficial TKI therapy.

Do professional boundaries limit trust?

The present study uses stories of mental health support workers talking about their relationship with clients to wonder about how trust might be limited by the professional boundaries of nursing. The writing arose out of an appreciative inquiry study looking at the role of mental health support workers. Participants talked about how they worked with their clients. As researchers, we were struck by the depth of trust that was built between worker and client. We have brought a phenomenological lens to wonder about the nature of trust, as shown in the data. The original research sought to identify what was working well for mental health support workers. The present study brings a phenomenological interpretive approach to four stories from the discovery phase of the study, with our thinking informed by Heidegger and van Manen. Interviews were conducted with 26 mental health support workers and six stakeholders in 2012-2103. For this paper, we drew from those transcripts stories of three mental health support workers and one stakeholder. Through a process of talking together, writing, and rewriting, we wondered about the meaning within these stories, with a strong focus on how trust was enacted. We saw that mental health support workers in this study, by not carrying the boundaries of being 'professional', seemed free to grow a stronger relationship of trust which was therapeutic. We ask: Is it time to rethink how professional boundaries limit the level of trust achieved with clients to the detriment of impactful care?

Using zebrafish to study the function of nephronophthisis and related ciliopathy genes.

Zebrafish are a valuable vertebrate model in which to study development and characterize genes involved in cystic kidney disease. Zebrafish embryos and larvae are transparent, allowing non-invasive imaging during their rapid development, which takes place over the first 72 hours post fertilisation. Gene-specific knockdown of nephronophthisis-associated genes leads to ciliary phenotypes which can be assessed in various developmental structures. Here we describe in detail the methods used for imaging cilia within Kupffer's vesicle to assess nephronophthisis and related ciliopathy phenotypes.

Nurses: A Voice to Lead.

The International Council of Nurses celebrates nurses' contributions to the Sustainable Development Goals.

Microscopic gastrointestinal stromal tumours: a clinical and molecular study of 13 cases.

AIMS: Recent literature suggests that clinically silent, microscopic gastrointestinal stromal tumours (micro-GISTs) are common incidental findings. The aim of this study was to examine the histological, immunohistochemical and molecular characteristics of these tumours, which we have defined as measuring ≤20 mm, in order to determine whether the rate and spectrum of mutations are similar to those of clinically symptomatic gastrointestinal stromal tumours (GISTs). METHODS AND RESULTS: Thirteen micro-GISTs identified as incidental findings in patients undergoing management of concomitant disease were tested for KIT/PDGFRA mutations. Ten micro-GISTs (77%) were located in the stomach, two (15%) in the duodenum, and one (8%) in the rectum. The mean tumour size was 9.3 mm (range 2-19 mm). All tumours were well-circumscribed lesions showing a predominantly spindle-cell morphology and a very low mitotic rate. Twelve of 13 (92%) tumours carried mutations in either KIT (83%) or PDGFRA (17%), a rate higher than in other published series. A high mutation rate (80%) was also seen in lesions measuring ≤5 mm. CONCLUSIONS: Our results suggest that KIT/PDGFRA mutation is a very common early event in GIST development, that tumour size does not reliably predict the presence of mutation, and that one or more subsequent mutations are required for clinical manifestation.