Crumbs 2 prevents cortical abnormalities in mouse dorsal telencephalon

AbstractThe formation of a functionally integrated nervous system is dependent on a highly organized sequence of events that includes timely division and differentiation of progenitors. Several apical polarity proteins have been shown to play crucial roles during neurogenesis, however, the role of Crumbs 2 (CRB2) in cortical development has not previously been reported.Here, we show that conditional ablation of Crb2 in the murine dorsal telencephalon leads to defects in the maintenance of the apical complex. Furthermore, within the mutant dorsal telencephalon there is premature expression of differentiation proteins. We examined the physiological function of Crb2 on wild type genetic background as well as on background lacking Crb1. Telencephalon lacking CRB2 resulted in reduced levels of PALS1 and CRB3 from the apical complex, an increased number of mitotic cells and expanded neuronal domain. These defects are transient and therefore only result in rather mild cortical abnormalities. We show that CRB2 is required for maintenance of the apical polarity complex during development of the cortex and regulation of cell division, and that loss of CRB2 results in cortical abnormalities

Retrospective cohort study of admission timing and mortality following COVID-19 infection in England.

OBJECTIVES: We investigated whether the timing of hospital admission is associated with the risk of mortality for patients with COVID-19 in England, and the factors associated with a longer interval between symptom onset and hospital admission. DESIGN: Retrospective observational cohort study of data collected by the COVID-19 Hospitalisation in England Surveillance System (CHESS). Data were analysed using multivariate regression analysis. SETTING: Acute hospital trusts in England that submit data to CHESS routinely. PARTICIPANTS: Of 14 150 patients included in CHESS until 13 May 2020, 401 lacked a confirmed diagnosis of COVID-19 and 7666 lacked a recorded date of symptom onset. This left 6083 individuals, of whom 15 were excluded because the time between symptom onset and hospital admission exceeded 3 months. The study cohort therefore comprised 6068 unique individuals. MAIN OUTCOME MEASURES: All-cause mortality during the study period. RESULTS: Timing of hospital admission was an independent predictor of mortality following adjustment for age, sex, comorbidities, ethnicity and obesity. Each additional day between symptom onset and hospital admission was associated with a 1% increase in mortality risk (HR 1.01; p<0.005). Healthcare workers were most likely to have an increased interval between symptom onset and hospital admission, as were people from Black, Asian and minority ethnic (BAME) backgrounds, and patients with obesity. CONCLUSION: The timing of hospital admission is associated with mortality in patients with COVID-19. Healthcare workers and individuals from a BAME background are at greater risk of later admission, which may contribute to reports of poorer outcomes in these groups. Strategies to identify and admit patients with high-risk and those showing signs of deterioration in a timely way may reduce the consequent mortality from COVID-19, and should be explored

Evidence against the proposition that “UK cancer survival statistics are misleading”: simulation study with National Cancer Registry data

Objectives To simulate each of two hypothesised errors in the National Cancer Registry (recording of the date of recurrence of cancer, instead of the date of diagnosis, for registrations initiated from a death certificate; long term survivors who are never notified to the registry), to estimate their possible effect on relative survival, and to establish whether lower survival in the UK might be due to one or both of these errors

Organisation of Prostate Cancer Services in the English National Health Service.

AIMS: The National Prostate Cancer Audit (NPCA) started in April 2013 with the aim of assessing the process of care and its outcomes in men diagnosed with prostate cancer in England and Wales. One of the key aims of the audit was to assess the configuration and availability of specialist prostate cancer services in England. MATERIALS AND METHODS: In 2014, the NPCA undertook an organisational survey of all 143 acute National Health Service (NHS) Trusts and 48 specialist multidisciplinary team (MDT) hubs cross England. Questionnaires established the availability and location of core diagnostic, treatment and patient-centred support services for the management of non-metastatic prostate cancer in addition to specific diagnostic and treatment procedures that reflect the continuing evolution of prostate cancer management, such as high-intensity focused ultrasound (HIFU) and stereotactic body radiotherapy. RESULTS: The survey received a 100% response rate. The results showed considerable geographical variation with respect to the availability of core treatment modalities, the size of the target population and catchment areas served by specialist MDT hubs, as well as in the uptake of additional procedures and services. Specifically there are gaps in the availability of core radiotherapy procedures; high dose rate and low dose rate brachytherapy are available in 44% and 75% of specialist MDTs, respectively. By comparison, there seems to be a relative 'over-penetration' of surgical innovation, with 67% of specialist MDTs providing robotic-assisted laparoscopic prostatectomy and 21% HIFU. There is also evidence of increased centralisation of core surgical procedures and regional inequity in the availability of surgical innovation across England. CONCLUSIONS: The organisational survey of the NPCA has provided a comprehensive assessment of the structure and function of specialist MDTs in England and the availability of prostate cancer procedures and services. As part of the prospective audit, the NPCA will assess the effect of the availability of prostate cancer services on access regionally and subsequent outcomes of care according to evidence-based guidelines

PREDICT: a new UK prognostic model that predicts survival following surgery for invasive breast cancer.

INTRODUCTION: The aim of this study was to develop and validate a prognostication model to predict overall and breast cancer specific survival for women treated for early breast cancer in the UK. METHODS: Using the Eastern Cancer Registration and Information Centre (ECRIC) dataset, information was collated for 5,694 women who had surgery for invasive breast cancer in East Anglia from 1999 to 2003. Breast cancer mortality models for oestrogen receptor (ER) positive and ER negative tumours were derived from these data using Cox proportional hazards, adjusting for prognostic factors and mode of cancer detection (symptomatic versus screen-detected). An external dataset of 5,468 patients from the West Midlands Cancer Intelligence Unit (WMCIU) was used for validation. RESULTS: Differences in overall actual and predicted mortality were <1% at eight years for ECRIC (18.9% vs. 19.0%) and WMCIU (17.5% vs. 18.3%) with area under receiver-operator-characteristic curves (AUC) of 0.81 and 0.79 respectively. Differences in breast cancer specific actual and predicted mortality were <1% at eight years for ECRIC (12.9% vs. 13.5%) and <1.5% at eight years for WMCIU (12.2% vs. 13.6%) with AUC of 0.84 and 0.82 respectively. Model calibration was good for both ER positive and negative models although the ER positive model provided better discrimination (AUC 0.82) than ER negative (AUC 0.75). CONCLUSIONS: We have developed a prognostication model for early breast cancer based on UK cancer registry data that predicts breast cancer survival following surgery for invasive breast cancer and includes mode of detection for the first time. The model is well calibrated, provides a high degree of discrimination and has been validated in a second UK patient cohort.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Diagnosing cancer in primary care: results from the National Cancer Diagnosis Audit

BACKGROUND: Continual improvements in diagnostic processes are needed to minimise the proportion of patients with cancer who experience diagnostic delays. Clinical audit is a means of achieving this. AIM: To characterise key aspects of the diagnostic process for cancer and to generate baseline measures for future re-audit. DESIGN AND SETTING: Clinical audit of cancer diagnosis in general practices in England. METHOD: Information on patient and tumour characteristics held in the English National Cancer Registry was supplemented by information from GPs in participating practices. Data items included diagnostic timepoints, patient characteristics, and clinical management. RESULTS: Data were collected on 17 042 patients with a new diagnosis of cancer during 2014 from 439 practices. Participating practices were similar to non-participating ones, particularly regarding population age, urban/rural location, and practice-based patient experience measures. The median diagnostic interval for all patients was 40 days (interquartile range [IQR] 15-86 days). Most patients were referred promptly (median primary care interval 5 days [IQR 0-27 days]). Where GPs deemed diagnostic delays to have occurred (22% of cases), patient, clinician, or system factors were responsible in 26%, 28%, and 34% of instances, respectively. Safety netting was recorded for 44% of patients. At least one primary care-led investigation was carried out for 45% of patients. Most patients (76%) had at least one existing comorbid condition; 21% had three or more. CONCLUSION: The findings identify avenues for quality improvement activity and provide a baseline for future audit of the impact of 2015 National Institute for Health and Care Excellence guidance on management and referral of suspected cancer

Effect of varying CRT refresh rate on the measurement of temporal summation.

Purpose To quantify the effect of cathode-tube-ray (CRT) monitor refresh rate on the measurement of the upper limit of complete temporal summation (critical duration) in the peripheral visual field of healthy observers. Methods Contrast thresholds were measured for seven achromatic spot stimuli (diameter 0.48°) of varying duration (nominal values: 10–200 ms) at an eccentricity of 8.8° along the 45°, 135°, 225° and 315° meridians of the visual field in three healthy, psychophysically experienced observers. Stimuli were presented on a CRT display with a refresh rate of 60 and 160 Hz. Contrast thresholds were expressed as contrast energy with stimulus durations being estimated using (1) the sum-of-frames (SOF) method and (2) Bridgeman's method incorporating measurements of phosphor persistence. Estimates of the critical duration were produced using iterative two-phase regression analysis. Results With stimulus duration expressed as SOF equivalent the critical duration was, on average, 10.6 ms longer with a refresh rate of 60 Hz (mean 45.7 ms, S.D. 10.1 ms) relative to 160 Hz (35.1 ms, S.D. 7.6 ms). When the Bridgeman method was used, minimal differences (1.8 ms) in critical duration values between the two refresh rates (60 Hz: 33.0 ms, S.D. 9.4 ms; 160 Hz: 31.2 ms, S.D. 7.0 ms) were observed. Identical trends were observed in all three subjects. Conclusions Psychophysical measurements of temporal summation are independent of variations in CRT refresh rate when the Bridgeman method, incorporating measured values of phosphor persistence, is used to estimate stimulus duration. This has significant implications for the specification of stimulus duration in psychophysical studies of vision employing conventional display monitors

Diagnosing cancer in primary care: results from the National Cancer Diagnosis Audit.

BACKGROUND: Continual improvements in diagnostic processes are needed to minimise the proportion of patients with cancer who experience diagnostic delays. Clinical audit is a means of achieving this. AIM: To characterise key aspects of the diagnostic process for cancer and to generate baseline measures for future re-audit. DESIGN AND SETTING: Clinical audit of cancer diagnosis in general practices in England. METHOD: Information on patient and tumour characteristics held in the English National Cancer Registry was supplemented by information from GPs in participating practices. Data items included diagnostic timepoints, patient characteristics, and clinical management. RESULTS: Data were collected on 17 042 patients with a new diagnosis of cancer during 2014 from 439 practices. Participating practices were similar to non-participating ones, particularly regarding population age, urban/rural location, and practice-based patient experience measures. The median diagnostic interval for all patients was 40 days (interquartile range [IQR] 15-86 days). Most patients were referred promptly (median primary care interval 5 days [IQR 0-27 days]). Where GPs deemed diagnostic delays to have occurred (22% of cases), patient, clinician, or system factors were responsible in 26%, 28%, and 34% of instances, respectively. Safety netting was recorded for 44% of patients. At least one primary care-led investigation was carried out for 45% of patients. Most patients (76%) had at least one existing comorbid condition; 21% had three or more. CONCLUSION: The findings identify avenues for quality improvement activity and provide a baseline for future audit of the impact of 2015 National Institute for Health and Care Excellence guidance on management and referral of suspected cancer