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BackgroundA new, more transmissible variant of SARS-CoV-2, variant of concern (VOC) 202012/01 or lineage B.1.1.7, has emerged in the UK. We estimate the risk of critical care admission, mortality in critical ill patients, and overall mortality associated with VOC B.1.1.7 compared with the original variant. We also compare clinical outcomes between these variants ‘ groups.MethodsWe linked a large primary care (QResearch), the national critical care (ICNARC CMP) and the COVID-19 testing (PHE) database and extracted two cohorts. The first was used to explore the association between VOC B.1.1.7 and critical care admission and 28-day mortality. The second to determine the risk of mortality in critically ill patients with VOC B.1.1.7 compared to those without. We used Royston-Parmar models adjusted for age, sex, region, other socio-demographics and comorbidities (asthma, COPD, type I and II, hypertension). We reported information on types and duration of organ supports for the two variants ‘ groups.FindingsThe first cohort included 198,420 patients. Of these, 80,494 had VOC B.1.1.7, 712 were critically ill and 630 died by 28 days. The second cohort included 3432 critically ill patients. Of these, 2019 had VOC B.1.1.7 and 822 died at the end of critical care. Using the first cohort, we estimated adjusted hazard ratios for critical care admission and mortality to be 1.99 (95% CI: 1.59, 2.49) and 1.59 (95% CI: 1.25-2.03) for VOC B.1.1.7 compared with the original variant group, respectively. The adjusted hazard ratio for mortality in critical care, estimated using the second cohort, was 0.93 (95% CI 0.76-1.15) for patients with VOC B.1.1.7, compared to those without.InterpretationVOC B.1.1.7 appears to be more severe. Patients with VOC B.1.1.7 are at increased risk of critical care admission and mortality compared with patients without. For patients receiving critical care, mortality appears independent of virus strain.RESEARCH IN CONTEXTEvidence before this studyA new variant of the SARS-CoV-2 virus, variant of concern (VOC) 202012/01, or lineage B.1.1.7, was detected in England in September 2020. The characteristics and outcomes of patients infected with VOC B.1.1.7 are not yet known. VOC B.1.1.7 has been associated with increased transmissibility. Early analyses have suggested infection with VOC B.1.1.7 may be associated with a higher risk of mortality compared with infection with other virus variants, but these analyses had either limited ability to adjust for key confounding variables or did not consider critical care admission. The effects of VOC B.1.1.7 on severe COVID-19 outcomes remain unclear.Added value of this studyThis study found a 60% higher risk of 28-day mortality associated with infection with VOC B.1.1.7 in patients tested in the community in comparison with the original variant, when adjusted for key confounding variables. The risk of critical care admission for those with VOC B.1.1.7 is double the risk associated with the original variant. For patients receiving critical care, the infecting variant is not associated with the risk of mortality at the end of critical care.Implications of all the available evidenceThe higher mortality and rate of critical care admission associated with VOC B.1.1.7, combined with its known increased transmissibility, are likely to put health care systems under further stress. These effects may be mitigated by the ongoing vaccination programme.

BackgroundPancreatic cancer has the worst survival rate among all cancers. Almost 70% of patients in the UK were diagnosed at Stage IV.AimThis study aimed to investigate the symptoms associated with the diagnoses of pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine neoplasms (PNEN), and comparatively characterise the symptomatology between the two tumour types to inform earlier diagnosis.Design and settingA nested case-control study in primary care was conducted using data from the QResearch® database. Patients aged ≥25 years and diagnosed with PDAC or PNEN during 2000 to 2019 were included as cases. Up to 10 controls from the same general practice were matched with each case by age, sex, and calendar year using incidence density sampling.MethodConditional logistic regression was used to investigate the association between the 42 shortlisted symptoms and the diagnoses of PDAC and (or) PNEN in different timeframes relative to the index date, adjusting for patients’ sociodemographic characteristics, lifestyle, and relevant comorbidities.ResultsA total of 23 640 patients were identified as diagnosed with PDAC and 596 with PNEN. Of the symptoms identified, 23 were significantly associated with PDAC, and nine symptoms with PNEN. The two alarm symptoms for both tumours were jaundice and gastrointestinal bleeding. The two newly identified symptoms for PDAC were thirst and dark urine. The risk of unintentional weight loss may be longer than 2 years before the diagnosis of PNEN.ConclusionPDAC and PNEN have overlapping symptom profiles. The QCancer® (pancreas) risk prediction model could be updated by including the newly identified symptoms and comorbidities, which could help GPs identify high-risk patients for timely investigation in primary care.

This article is the study protocol and statistical analysis plan for the project. This study is set up to identify and quantify “red flag” symptoms associated with the diagnosis of Pancreatic Neuroendocrine Neoplasm (PNEN) and compare these with the symptoms associated with Pancreatic Ductal Adenocarcinoma (PDAC). The results of this study will inform the evidence base for the refinement of the QCancer (Pancreas) tools, which have been integrated into the UK NHS primary care computer systems, to improve the early recognition of PNEN.

Rationale and Objectives Noncontrast magnetic resonance angiography (NC-MRA) of pedal artery remains challenging because of the global and regional disease load, tissue integrity, and altered microcirculation. This study aims to investigate the feasibility of the NC-MRA of pedal arteries with flow-sensitive dephasing–prepared steady-state free precession (FSD-SSFP) and to explore the effect of disease load of type II diabetes on the vessel depiction. Materials and Methods FSD-SSFP was performed on a 1.5-T magnetic resonance system before the contrast-enhanced MRA (CE-MRA) as a reference standard in 39 consecutive diabetic subjects (29 men and 16 women, aged 57.9 ± 11.4 years). Two experienced radiologists evaluated the overall artery visibility (VA) and the contamination from soft tissue (SC) and veins (VC) with a four-point scale. Chronic complications and measures including random blood glucose (RBG), lipid panel, body mass index, risk of diabetic foot ulcers (RDF), and glycated hemoglobin (HbA1c) by the imaging were recorded as disease load indicators. Spearman rank correlation and ordinal regression were performed to investigate the effect of disease load on the depiction of pedal arteries. Results The measurement of RBG and RDF were significantly correlated with the VC in CE-MRA and with the overall visibility of pedal arteries in NC-MRA ( P P P P P 1 value that ranged from 70 to 160 mT⋅ms 2 /m (mean, 125 ± 18 mT⋅ms 2 /m) in this study. Conclusions FSD-SSFP proved to be a useful modality of NC-MRA for pedal artery imaging in diabetic patients. The vessel depiction is subject to the local and systemic disease load of type II diabetes. Technical optimization of the flow-sensitive dephasing gradient moment and properly choosing candidate would help augment the potential of this technique in patient care of peripheral artery disease.

Rationale and Objectives Differentiating mild cognitive impairment (MCI) and Alzheimer Disease (AD) from healthy aging remains challenging. This study aimed to explore the cerebral structural alterations of subjects with MCI or AD as compared to healthy elderly based on the individual and collective effects of cerebral morphologic indices using univariate and multivariate analyses. Materials and Methods T1-weighted images (T1WIs) were retrieved from Alzheimer Disease Neuroimaging Initiative database for 116 subjects who were categorized into groups of healthy aging, MCI, and AD. Analysis of covariance (ANCOVA) and multivariate analysis of covariance (MANCOVA) were performed to explore the intergroup morphologic alterations indexed by surface area, curvature index, cortical thickness, and subjacent white matter volume with age and sex controlled as covariates, in 34 parcellated gyri regions of interest (ROIs) for both cerebral hemispheres based on the T1WI. Statistical parameters were mapped on the anatomic images to facilitate visual inspection. Results Global rather than region-specific structural alterations were revealed in groups of MCI and AD relative to healthy elderly using MANCOVA. ANCOVA revealed that the cortical thickness decreased more prominently in entorhinal, temporal, and cingulate cortices and was positively correlated with patients' cognitive performance in AD group but not in MCI. The temporal lobe features marked atrophy of white matter during the disease dynamics. Significant intercorrelations were observed among the morphologic indices with univariate analysis for given ROIs. Conclusions Significant global structural alterations were identified in MCI and AD based on MANCOVA model with improved sensitivity. The intercorrelation among the morphologic indices may dampen the use of individual morphological parameter in featuring cerebral structural alterations. Decrease in cortical thickness is not reflective of the cognitive performance at the early stage of AD.

Laterality of human brain varies under healthy aging and diseased conditions. The alterations in hemispheric asymmetry may embed distinct biomarkers linked to the disease dynamics. Statistical parametric mapping based on high-resolution magnetic resonance imaging (MRI) and image processing techniques have allowed automated characterization of morphological features across the entire brain. In this study, 149 subjects grouped in healthy young, healthy elderly, mild cognitive impairment (MCI), and Alzheimer's disease (AD) were investigated using multivariate analysis for regional cerebral laterality indexed by surface area, curvature index, cortical thickness, and subjacent white matter volume measured on high-resolution MR images. Asymmetry alteration of MCI and AD were characterized by marked region-specific reduction, while healthy elderly featured a distinct laterality shift in the limbic system in addition to regional asymmetry loss. Lack of the laterality shift in limbic system and early loss of asymmetry in entorhinal cortex may be biomarkers to identify preclinical AD among other dementia. Multivariate analysis of hemispheric asymmetry may provide information helpful for monitoring the disease progress and improving the management of MCI and AD.

BackgroundHeterogeneous disease trajectories of mild cognitive impairment (MCI) and dementia are frequently encountered in clinical practice, but there is still insufficient knowledge to understand the reasons and mechanisms causing this heterogeneity. In addition to correlates of the disorder, patient characteristics such as their health status, social environment, comorbidities and frailty may contribute to variability in trajectories over time. The current paper outlines the study design and the study population of and provides an overview of the data collected in the Clinical Course of Cognition and Comorbidity in Mild Cognitive Impairment (4C-MCI cohort, n = 315) and Dementia (4C-Dementia cohort, n = 331) Study.MethodsThe two complementary longitudinal cohorts part of the 4C study began enrolment in March 2010. Participants were prospectively recruited from three collaborating Dutch Alzheimer Centers, with three annual follow-up assessments after baseline. Extensive neuropsychological assessments, and detailed profiling of comorbidities, health and frailty at each follow up were the key features of the 4C study. As such, the 4C study was designed to study if and how patients’ comorbidities and frailty are associated with the course of MCI and dementia measured with a comprehensive and multidimensional set of outcomes including cognition, daily functioning, quality of life, behavioral disturbances, caregiver burden, institutionalization and death and whether the effects of medical health and frailty differ between MCI and dementia stages of cognitive disorders.ConclusionSampled in a clinical setting, the 4C study complements population-based studies on neurodegenerative disorders in terms of the type of assessment (e.g. comorbidity, frailty, and functional status were repeatedly assessed). The 4C study complements available clinical cohorts of MCI and dementia patients, because the exclusion criteria were kept to a minimum, to obtain a sample that is representative for the average patient visiting a memory clinic.