The Barts Health NHS Trust COVID-19 cohort: characteristics, outcomes and risk scoring of patients in East London.

BACKGROUND: Barts Health National Health Service Trust (BHNHST) serves a diverse population of 2.5 million people in London, UK. We undertook a health services assessment of factors used to evaluate the risk of severe acute respiratory coronavirus 2 (SARS-CoV-2) infection.METHODS: Patients with confirmed polymerase chain reaction (PCR) test results admitted between 1 March and 1 August 2020 were included, alongwith clinician-diagnosed suspected cases. Prognostic factors from the 4C Mortality score and 4C Deterioration scores were extracted from electronic health records and logistic regression was used to quantify the strength of association with 28-day mortality and clinical deterioration using national death registry linkage.RESULTS: Of 2783 patients, 1621 had a confirmed diagnosis, of whom 61% were male and 54% were from Black and Minority Ethnic groups; 26% died within 28 days of admission. Mortality was strongly associated with older age. The 4C mortality score had good stratification of risk with a calibration slope of 1.14 (95% CI 1.01-1.27). It may have under-estimated mortality risk in those with a high respiratory rate or requiring oxygen.CONCLUSION: Patients in this diverse patient cohort had similar mortality associated with prognostic factors to the 4C score derivation sample, but survival might be poorer in those with respiratory failure.

A systematic review and meta-analysis of the diagnostic accuracy of biparametric prostate MRI for prostate cancer in men at risk.

INTRODUCTION: Multiparametric magnetic resonance imaging (mpMRI), the use of three multiple imaging sequences, typically T2-weighted, diffusion weighted (DWI) and dynamic contrast enhanced (DCE) images, has a high sensitivity and specificity for detecting significant cancer. Current guidance now recommends its use prior to biopsy. However, the impact of DCE is currently under debate regarding test accuracy. Biparametric MRI (bpMRI), using only T2 and DWI has been proposed as a viable alternative. We conducted a contemporary systematic review and meta-analysis to further examine the diagnostic performance of bpMRI in the diagnosis of any and clinically significant prostate cancer. METHODS: A systematic review of the literature from 01/01/2017 to 06/07/2019 was performed by two independent reviewers using predefined search criteria. The index test was biparametric MRI and the reference standard whole-mount prostatectomy or prostate biopsy. Quality of included studies was assessed by the QUADAS-2 tool. Statistical analysis included pooled diagnostic performance (sensitivity; specificity; AUC), meta-regression of possible covariates and head-to-head comparisons of bpMRI and mpMRI where both were performed in the same study. RESULTS: Forty-four articles were included in the analysis. The pooled sensitivity for any cancer detection was 0.84 (95% CI, 0.80-0.88), specificity 0.75 (95% CI, 0.68-0.81) for bpMRI. The summary ROC curve yielded a high AUC value (AUC = 0.86). The pooled sensitivity for clinically significant prostate cancer was 0.87 (95% CI, 0.78-0.93), specificity 0.72 (95% CI, 0.56-0.84) and the AUC value was 0.87. Meta-regression analysis revealed no difference in the pooled diagnostic estimates between bpMRI and mpMRI. CONCLUSIONS: This meta-analysis on contemporary studies shows that bpMRI offers comparable test accuracies to mpMRI in detecting prostate cancer. These data are broadly supportive of the bpMRI approach but heterogeneity does not allow definitive recommendations to be made. There is a need for prospective multicentre studies of bpMRI in biopsy naïve men.

PROMIS--Prostate MR imaging study: A paired validating cohort study evaluating the role of multi-parametric MRI in men with clinical suspicion of prostate cancer.

BACKGROUND: Transrectal ultrasound-guided prostate biopsies are prone to detection errors. Multi-parametric MRI (MP-MRI) may improve the diagnostic pathway. METHODS: PROMIS is a prospective validating paired-cohort study that meets criteria for level 1 evidence in diagnostic test evaluation. PROMIS will investigate whether multi-parametric (MP)-MRI can discriminate between men with and without clinically-significant prostate cancer who are at risk prior to first biopsy. Up to 714 men will have MP-MRI (index), 10-12 core TRUS-biopsy (standard) and 5mm transperineal template mapping (TPM) biopsies (reference). The conduct and reporting of each test will be blinded to the others. RESULTS: PROMIS will measure and compare sensitivity, specificity, and positive and negative predictive values of both MP-MRI and TRUS-biopsy against TPM biopsies. The MP-MRI results will be used to determine the proportion of men who could safely avoid biopsy without compromising detection of clinically-significant cancers. For the primary outcome, significant cancer on TPM is defined as Gleason grade >/= 4+3 and/or maximum cancer core length of ≥ 6 mm. PROMIS will also assess inter-observer variability among radiologists among other secondary outcomes. Cost-effectiveness of MP-MRI prior to biopsy will also be evaluated. CONCLUSIONS: PROMIS will determine whether MP-MRI of the prostate prior to first biopsy improves the detection accuracy of clinically-significant cancer.

Effect of combining anesthetics in neonates on long-term cognitive function.

BACKGROUND: With growing evidence that anesthesia exposure in infancy affects cognitive development, it is important to understand how distinct anesthetic agents and combinations can alter long-term memory. Investigations of neuronal death suggest that combining anesthetic agents increases the extent of neuronal injury. However, it is unclear how the use of simultaneously combined anesthetics affects cognitive outcome relative to the use of a single agent. METHODS: Postnatal day 7 (P7) male rats were administered either sevoflurane as a single agent or the combined delivery of sevoflurane with nitrous oxide at 1 Minimum Alveolar Concentration for 4 h. Behavior was assessed in adulthood using the forced alternating T-maze, social recognition, and context-specific object recognition tasks. RESULTS: Animals exposed to either anesthetic were unimpaired in the forced alternating T-maze test and had intact social recognition. Subjects treated with the combined anesthetic displayed a deficit, however, in the object recognition task, while those treated with sevoflurane alone were unaffected. CONCLUSION: A combined sevoflurane and nitrous oxide anesthetic led to a distinct behavioral outcome compared with sevoflurane alone, suggesting that the simultaneous use of multiple agents may uniquely influence early neural and cognitive development and potentially impacts associative memory.

Clinical and biological significance of CXCL12 and CXCR4 expression in adult testes and germ cell tumours of adults and adolescents.

Interaction between the chemokine CXCL12 (SDF1) and the G-protein coupled receptor CXCR4 is responsible for the maintenance of adult stem cell niches and is known to play an important role in utero in the migration of primordial germ cells. We demonstrate expression of CXCL12 by Sertoli cells and confirm CXCR4 expression by the germ cell population of the adult human testes. CXCR4 is also known to mediate organ-specific patterns of metastases in a range of common cancers. We identify consistent expression of CXCR4 mRNA and protein in testicular germ cell tumours (TGCT) that accounts for their patterns of relapse in sites of known CXCL12 expression. Extragonadal primary germ cell tumours express CXCR4 and their sites of occurrence are coincident with areas of known CXCL12 expression in utero. We show that CXCL12 stimulates the invasive migration of a TGCT cell line in vitro in a CXCR4-dependent fashion and activates ERK. Furthermore, we demonstrate that expression of CXCL12 in stage I non-seminomas is significantly associated with organ-confined disease post-orchidectomy and reduced risk of relapse (p = 0.003). This may be through the loss of CXCL12 gradients that might otherwise attract cells away from the primary tumour. We propose CXCL12 expression as a potential predictor of subsequent relapse that could lead to avoiding unnecessary treatment and associated late toxicities. Our observations support a role for CXCL12/CXCR4 in the adult germ cell population and demonstrate pathological function in germ cell tumour development and metastasis that may have clinical utility.

A case-control study to estimate the impact of the Icelandic population-based mammography screening program on breast cancer death.

BACKGROUND: The Icelandic breast cancer screening program, initiated November 1987 in Reykjavik and covering the whole country from December 1989, comprises biennial invitation to mammography for women aged 40-69 years old. PURPOSE: To estimate the impact of mammography service screening in Iceland on deaths from breast cancer. MATERIAL AND METHODS: Cases were deaths from breast cancer from 1990 onwards in women aged 40 and over at diagnosis, during the period November 1987 to December 31, 2002. Age- and screening-area-matched, population-based controls were women who had also been invited to screening but were alive at the time their case died. RESULTS: Using conditional logistic regression on the data from 226 cases and 902 controls, the odds ratio for the risk of death from breast cancer in those attending at least one screen compared to those never screened was 0.59 (95% CI 0.41-0.84). After adjustment for healthy-volunteer bias and screening-opportunity bias, the odds ratio was 0.65 (95% CI 0.39-1.09). CONCLUSION: These results indicate a 35-40% reduction in breast cancer deaths by attending the Icelandic breast cancer screening program. These results are consistent with the overall evidence from other observational evaluations of mammography-based programs.

What should the detection rates of cancers be in breast screening programmes?

Minimum detection rates at screening are sometimes laid down as standards for breast cancer screening programmes, based on underlying incidence of the disease in the age group screened. Detection rates should also depend on desired sensitivity, mean sojourn time, interscreening interval and the screening round--that is, prevalent (first) or incident (second or subsequent). In this paper, we use these quantities to derive expected, minimum and maximum detection rates proportional to the underlying incidence as well as estimated underlying incidence rates from extrapolation of prescreening trends in England and Wales to derive alternative standard minimum, expected and maximum detection rates per 1000 women screened for the UK Breast Screening Programme, as follows: minimum detection rates should be 4.1 and 4.3 at prevalence screen and incidence screens, respectively; expected rates should be 6.9 and 4.8 and maximum rates of 9.6 and 5.5. These are consistent with observed detection rates in the UK programme.