Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial

BackgroundAnterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability.MethodsWe did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score—4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367.FindingsBetween Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5–13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications.InterpretationSurgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management

Evidence synthesis to inform model-based cost-effectiveness evaluations of diagnostic tests: a methodological systematic review of health technology assessments

Background: Evaluations of diagnostic tests are challenging because of the indirect nature of their impact on patient outcomes. Model-based health economic evaluations of tests allow different types of evidence from various sources to be incorporated and enable cost-effectiveness estimates to be made beyond the duration of available study data. To parameterize a health-economic model fully, all the ways a test impacts on patient health must be quantified, including but not limited to diagnostic test accuracy. Methods: We assessed all UK NIHR HTA reports published May 2009-July 2015. Reports were included if they evaluated a diagnostic test, included a model-based health economic evaluation and included a systematic review and meta-analysis of test accuracy. From each eligible report we extracted information on the following topics: 1) what evidence aside from test accuracy was searched for and synthesised, 2) which methods were used to synthesise test accuracy evidence and how did the results inform the economic model, 3) how/whether threshold effects were explored, 4) how the potential dependency between multiple tests in a pathway was accounted for, and 5) for evaluations of tests targeted at the primary care setting, how evidence from differing healthcare settings was incorporated. Results: The bivariate or HSROC model was implemented in 20/22 reports that met all inclusion criteria. Test accuracy data for health economic modelling was obtained from meta-analyses completely in four reports, partially in fourteen reports and not at all in four reports. Only 2/7 reports that used a quantitative test gave clear threshold recommendations. All 22 reports explored the effect of uncertainty in accuracy parameters but most of those that used multiple tests did not allow for dependence between test results. 7/22 tests were potentially suitable for primary care but the majority found limited evidence on test accuracy in primary care settings. Conclusions: The uptake of appropriate meta-analysis methods for synthesising evidence on diagnostic test accuracy in UK NIHR HTAs has improved in recent years. Future research should focus on other evidence requirements for cost-effectiveness assessment, threshold effects for quantitative tests and the impact of multiple diagnostic tests

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Expression of hippocampal brain-derived neurotrophic factor and its receptors in Stanley consortium brains

Several lines of evidence implicate BDNF in the pathophysiology of psychiatric illness. BDNF polymorphisms have also been associated with the risk of schizophrenia and mood disorders. We therefore investigated whether levels of (pro)BDNF and receptor proteins, TrkB and p75, are altered in hippocampus in schizophrenia and mood disorder and whether polymorphisms in each gene influenced protein expression. Formalin-fixed paraffin-embedded hippocampal sections from subjects with schizophrenia, major depressive disorder (MDD), bipolar disorder (BPD) and non-psychiatric controls were obtained from the Stanley Foundation Neuropathology Consortium. (pro)BDNF, TrkB(T1) and p75 protein densities were quantified by immunoautoradiography and DNA extracted from each subject was used to determine the effect of genotype on protein expression. In MDD, reductions in (pro)BDNF were seen in all layers of the right but not the left hippocampus with no changes in the dentate gyrus. The pattern was similar but less marked for BPD. In addition, BPD but not MDD patients, had bilateral reductions in p75 in hippocampal layers but not in dentate gyrus. No changes in TrkB(T1) density were seen in any diagnosis. These findings suggest MDD and BPD may share impairment in (pro)BDNF expression. However, BPD may involve impairments of both (pro)BDNF and p75 receptor, whereas MDD may involve impaired (pro)BDNF alone. Moreover, the lateralisation of changes may indicate a role of asymmetry in vulnerability to MDD. Hippocampal (pro)BDNF and receptor levels were also affected by genotype, suggesting that allelic variations are important in the hippocampal abnormalities seen in these psychiatric disorders

NMDA receptor subunit NRI and postsynaptic protein PSD-95 in hippocampus and orbitofrontal cortex in schizophrenia and mood disorder

Much interest has focussed on glutamate and the N-Methyl-D-Aspartate (NMDA) glutamate receptor in the pathogenesis of schizophrenia. A number of studies have reported abnormal gene transcription of various glutamate receptor subtypes in the hippocampus including the NMDA receptor. However, corresponding protein levels in subregions of the hippocampus have not yet been investigated. We have used immunoautoradiographical techniques to assess the expression of the obligatory NMDA receptor subunit NR1 and an associated post-synaptic density protein PSD-95 in the hippocampal dentate gyrus and orbitofrontal cortex (OFC) in schizophrenia and mood disorder. Optical density measures from film autoradiographs revealed no changes in NR1 or PSD-95 in the OFC or dentate hilus, however a decrease in PSD-95 was found in the dentate molecular layer in both schizophrenia and bipolar disorder relative to major depression. These findings were unrelated to antipsychotic or mood stabilizer drug treatment. The dentate molecular layer contains the dendritic trees of granule cells and is the target of major excitatory afferent inputs from associative cortical, parahippocampal and hippocampal regions. A reduction in PSD-95 at glutamate synapses of the molecular layer may have a deleterious impact on information flow to other hippocampal regions via granule cells and their projecting mossy fibres. A down-regulation of PSD-95 in schizophrenia and bipolar disorder may also relate to disease mechanisms of psychosis

Abnormal expression of post-synaptic proteins in prefrontal cortex of patients with schizophrenia

There is converging evidence of dendritic spine dysfunction in schizophrenia. In the present study we hypothesized that the expression of key proteins involved in dendritic spine development and stability may be affected in schizophrenia. Postmortem frontal cortex (BA6) from patients with schizophrenia, major depressive disorder, bipolar disorder and healthy controls was processed for glutamate post-synaptic fraction extraction and post-synaptic density purification. Protein expression of the post-synaptic fraction and the post-synaptic density was assessed using immunoprecipitation and Western blotting respectively. The expression of the N-methyl-d-aspartate glutamate receptor (NMDAR) subunit NR2A, post-synaptic density 95 (PSD-95), Ca2+/calmodulin-dependent protein kinase II subunits α and β (CaMKIIα and β) were significantly reduced in schizophrenia. A significant decrease in the expression of NR2A was also observed in patients with major depressive disorder relative to controls, but not in patients with bipolar disorder. These results add to existing evidence for disturbed post-synaptic glutamate function and synaptic plasticity in schizophrenia. There may also be subtle disturbances in the post-synaptic glutamatergic function in major depressive disorder