The utility of diagnostic selective nerve root blocks in the management of patients with lumbar radiculopathy: a systematic review.

OBJECTIVE: Lumbar radiculopathy (LR) often manifests as pain in the lower back radiating into one leg (sciatica). Unsuccessful back surgery is associated with significant healthcare costs and risks to patients. This review aims to examine the diagnostic accuracy of selective nerve root blocks (SNRBs) to identify patients most likely to benefit from lumbar decompression surgery. DESIGN: Systematic review of diagnostic test accuracy studies. ELIGIBILITY CRITERIA: Primary research articles using a patient population with low back pain and symptoms in the leg, SNRB administered under radiological guidance as index test, and any reported reference standard for the diagnosis of LR. INFORMATION SOURCES: MEDLINE (Ovid), MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Science Citation Index, Biosis, LILACS, Dissertation abstracts and National Technical Information Service from inception to 2018. METHODS: Risk of bias and applicability was assessed using the QUADAS-2 tool. We performed random-effects logistic regression to meta-analyse studies grouped by reference standard. RESULTS: 6 studies (341 patients) were included in this review. All studies were judged at high risk of bias. There was substantial heterogeneity across studies in sensitivity (range 57%-100%) and specificity (10%-86%) estimates. Four studies were diagnostic cohort studies that used either intraoperative findings during surgery (pooled sensitivity: 93.5% [95% CI 84.0 to 97.6]; specificity: 50.0% [16.8 to 83.2]) or 'outcome following surgery' as the reference standard (pooled sensitivity: 90.9% [83.1 to 95.3]; specificity 22.0% [7.4 to 49.9]). Two studies had a within-patient case-control study design, but results were not pooled because different types of control injections were used. CONCLUSIONS: We found limited evidence which was of low methodological quality indicating that the diagnostic accuracy of SNRB is uncertain and that specificity in particular may be low. SNRB is a safe test with a low risk of clinically significant complications, but it remains unclear whether the additional diagnostic information it provides justifies the cost of the test.National Institute for Health Research Health Technology Assessment programme grant (project number 09/111/01)

Development and external validation of a clinical prediction model to aid coeliac disease diagnosis in primary care:an observational study

BACKGROUND: Coeliac disease (CD) affects approximately 1% of the population, although only a fraction of patients are diagnosed. Our objective was to develop diagnostic prediction models to help decide who should be offered testing for CD in primary care. METHODS: Logistic regression models were developed in Clinical Practice Research Datalink (CPRD) GOLD (between Sep 9, 1987 and Apr 4, 2021, n=107,075) and externally validated in CPRD Aurum (between Jan 1, 1995 and Jan 15, 2021, n=227,915), two UK primary care databases, using (and controlling for) 1:4 nested case-control designs. Candidate predictors included symptoms and chronic conditions identified in current guidelines and using a systematic review of the literature. We used elastic-net regression to further refine the models. FINDINGS: The prediction model included 24, 24, and 21 predictors for children, women, and men, respectively. For children, the strongest predictors were type 1 diabetes, Turner syndrome, IgA deficiency, or first-degree relatives with CD. For women and men, these were anaemia and first-degree relatives. In the development dataset, the models showed good discrimination with a c-statistic of 0·84 (95% CI 0·83–0·84) in children, 0·77 (0·77–0·78) in women, and 0·81 (0·81–0·82) in men. External validation discrimination was lower, potentially because ‘first-degree relative’ was not recorded in the dataset used for validation. Model calibration was poor, tending to overestimate CD risk in all three groups in both datasets. INTERPRETATION: These prediction models could help identify individuals with an increased risk of CD in relatively low prevalence populations such as primary care. Offering a serological test to these patients could increase case finding for CD. However, this involves offering tests to more people than is currently done. Further work is needed in prospective cohorts to refine and confirm the models and assess clinical and cost effectiveness. FUNDING: National Institute for Health Research Health Technology Assessment Programme (grant number NIHR129020

T cell immunosenescence after early life adversity: association with cytomegalovirus infection.

Early life adversity (ELA) increases the risk for multiple age-related diseases, such as diabetes type 2 and cardiovascular disease. As prevalence is high, ELA poses a major and global public health problem. Immunosenescence, or aging of the immune system, has been proposed to underlie the association between ELA and long-term health consequences. However, it is unclear what drives ELA-associated immunosenescence and which cells are primarily affected. We investigated different biomarkers of immunosenescence in a healthy subset of the EpiPath cohort. Participants were either parent-reared (Ctrl, n = 59) or had experienced separation from their parents in early childhood and were subsequently adopted (ELA, n = 18). No difference was observed in telomere length or in methylation levels of age-related CpGs in whole blood, containing a heterogeneous mixture of immune cells. However, when specifically investigating T cells, we found a higher expression of senescence markers (CD57) in ELA. In addition, senescent T cells (CD57+) in ELA had an increased cytolytic potential compared to senescent cells in controls. With a mediation analysis we demonstrated that cytomegalovirus (CMV) infection, which is an important driving force of immunosenescence, largely accounted for elevated CD57 expression observed in ELA. Leukocyte telomere length may obscure cell-specific immunosenescence; here, we demonstrated that the use of cell surface markers of senescence can be more informative. Our data suggest that ELA may increase the risk of CMV infection in early childhood, thereby mediating the effect of ELA on T cell-specific immunosenescence. Thus, future studies should include CMV as a confounder or selectively investigate CMV seronegative cohorts

Accuracy of potential diagnostic indicators for coeliac disease:a systematic review protocol

INTRODUCTION: Coeliac disease (CD) is a systemic immune-mediated disorder triggered by gluten in genetically predisposed individuals. CD is diagnosed using a combination of serology tests and endoscopic biopsy of the small intestine. However, because of non-specific symptoms and heterogeneous clinical presentation, diagnosing CD is challenging. Early detection of CD through improved case-finding strategies can improve the response to a gluten-free diet, patients' quality of life and potentially reduce the risk of complications. However, there is a lack of consensus in which groups may benefit from active case-finding. METHODS AND ANALYSIS: We will perform a systematic review to determine the accuracy of diagnostic indicators (such as symptoms and risk factors) for CD in adults and children, and thus can help identify patients who should be offered CD testing. MEDLINE, Embase, Cochrane Library and Web of Science will be searched from 1997 until 2020. Screening will be performed in duplicate. Data extraction will be performed by one and checked by a second reviewer. Disagreements will be resolved through discussion or referral to a third reviewer. We will produce a narrative summary of identified prediction models. Studies, where 2×2 data can be extracted or reconstructed, will be treated as diagnostic accuracy studies, that is, the diagnostic indicators are the index tests and CD serology and/or biopsy is the reference standard. For each diagnostic indicator, we will perform a bivariate random-effects meta-analysis of the sensitivity and specificity. ETHICS AND DISSEMINATION: Results will be reported in peer-reviewed journals, academic and public presentations and social media. We will convene an implementation panel to advise on the optimum strategy for enhanced dissemination. We will discuss findings with Coeliac UK to help with dissemination to patients. Ethical approval is not applicable, as this is a systematic review and no research participants will be involved. PROSPERO REGISTRATION NUMBER: CRD42020170766

COVID-19 trajectories among 57 million adults in England: a cohort study using electronic health records

BACKGROUND: Updatable estimates of COVID-19 onset, progression, and trajectories underpin pandemic mitigation efforts. To identify and characterise disease trajectories, we aimed to define and validate ten COVID-19 phenotypes from nationwide linked electronic health records (EHR) using an extensible framework. METHODS: In this cohort study, we used eight linked National Health Service (NHS) datasets for people in England alive on Jan 23, 2020. Data on COVID-19 testing, vaccination, primary and secondary care records, and death registrations were collected until Nov 30, 2021. We defined ten COVID-19 phenotypes reflecting clinically relevant stages of disease severity and encompassing five categories: positive SARS-CoV-2 test, primary care diagnosis, hospital admission, ventilation modality (four phenotypes), and death (three phenotypes). We constructed patient trajectories illustrating transition frequency and duration between phenotypes. Analyses were stratified by pandemic waves and vaccination status. FINDINGS: Among 57 032 174 individuals included in the cohort, 13 990 423 COVID-19 events were identified in 7 244 925 individuals, equating to an infection rate of 12·7% during the study period. Of 7 244 925 individuals, 460 737 (6·4%) were admitted to hospital and 158 020 (2·2%) died. Of 460 737 individuals who were admitted to hospital, 48 847 (10·6%) were admitted to the intensive care unit (ICU), 69 090 (15·0%) received non-invasive ventilation, and 25 928 (5·6%) received invasive ventilation. Among 384 135 patients who were admitted to hospital but did not require ventilation, mortality was higher in wave 1 (23 485 [30·4%] of 77 202 patients) than wave 2 (44 220 [23·1%] of 191 528 patients), but remained unchanged for patients admitted to the ICU. Mortality was highest among patients who received ventilatory support outside of the ICU in wave 1 (2569 [50·7%] of 5063 patients). 15 486 (9·8%) of 158 020 COVID-19-related deaths occurred within 28 days of the first COVID-19 event without a COVID-19 diagnoses on the death certificate. 10 884 (6·9%) of 158 020 deaths were identified exclusively from mortality data with no previous COVID-19 phenotype recorded. We observed longer patient trajectories in wave 2 than wave 1. INTERPRETATION: Our analyses illustrate the wide spectrum of disease trajectories as shown by differences in incidence, survival, and clinical pathways. We have provided a modular analytical framework that can be used to monitor the impact of the pandemic and generate evidence of clinical and policy relevance using multiple EHR sources. FUNDING: British Heart Foundation Data Science Centre, led by Health Data Research UK