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We lead multidisciplinary applied research and training to rethink the way health care is delivered in general practice and across the community.
Comparing the incidence of common adverse events of interest following influenza vaccination in the first season adjuvanted trivalent immunisation was introduced: English sentinel network annual report paper 2018/19 (Preprint)
<sec> <title>BACKGROUND</title> <p>Vaccination is the most effective form of prevention of seasonal influenza; the UK has a national influenza vaccination programme to cover targeted population groups. Influenza vaccines are known to be associated with some common minor adverse events of interest (AEIs), but it is not known if the adjuvanted trivalent influenza vaccine (aTIV), first offered in the 2018/19 season) would be associated with more AEIs than other types of vaccines.</p> </sec> <sec> <title>OBJECTIVE</title> <p>We aim to compare the incidence of AEIs associated with different types of seasonal influenza vaccines offered in the 2018/19 season.</p> </sec> <sec> <title>METHODS</title> <p>We carried out a retrospective cohort study using computerised medical record data from the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) sentinel network database. We extracted data on vaccine exposure and consultations for European Medicines Agency (EMA)-specified AEIs for the 2018/19 influenza season. We used a self-controlled case series design and computed relative incidence (RI) of AEIs following vaccination, and compared the incidence of AEIs associated with aTIV, quadrivalent influenza vaccine (QIV) and live attenuated influenza vaccine (LAIV). We also compared the incidence of AEIs for vaccinations that took place in a practice with those that took place elsewhere.</p> </sec> <sec> <title>RESULTS</title> <p>A total of 1,024,160 individuals received a seasonal influenza vaccine, of which 165,723 individuals reported a total of 283,355 compatible symptoms in the 2018/19 season. The majority of AEIs occurred within seven days following vaccination, with a seasonal effect observed. Using aTIV as the reference group, QIV was associated with a higher RI of AEIs (RI=1.46, 95% CI 1.41-1.52), whereas LAIV was associated with a lower RI of AEIs (RI=0.79, 95% CI 0.73-0.83). No effect of vaccination setting on the incidence of AEIs was observed.</p> </sec> <sec> <title>CONCLUSIONS</title> <p>Routine sentinel network data offer an opportunity to make comparisons between safety profiles of different vaccines. Evidence that supports the safety of newer types of vaccines may be reassuring for patients and could help improve uptake in the future.</p> </sec> <sec> <title>CLINICALTRIAL</title> <p /> </sec>
Will policy to constrain GP referrals damage health? Evidence using practice level NHS emergency admissions administrative data
© 2021 Elsevier Ltd Attempts to control hospital expenditure by managing down General Practitioner (GP) referrals are reoccurring features of UK health policy. However, despite the best efforts of GPs to benchmark referral criteria, patient health may be damaged and other costs created by constraining referrals to targets. This paper adopts an indirect method to indicate whether rationing practice referrals may damage population health by distorting the use of health resources away from patients’ interests. We utilise a comprehensive database at practice level that allows us to explore the relationship between referrals and emergency admissions, using a panel fixed effects model of admissions that allows for the endogeneity of referrals. We find that practice referrals are positively and partially correlated with emergency admissions, which is consistent with time-varying practice-level sickness shocks driving the relationship between referrals and emergency care, rather than shocks to the practice willingness to refer, or to system reforms. In this environment, government policy to constrain referrals may make the elective care less responsive to practice-level variations in illness, and thereby lower health.
Association of weight changes with changes in histological features and blood markers in non-alcoholic steatohepatitis
<p><strong>Background and aims:</strong> Weight loss is recommended for patients with non-alcoholic steatohepatitis (NASH) but the impact of weight change on disease activity remains unclear. We examined the association between weight change (gain/loss) and changes in biochemical and histological features of NASH.</p> <p><strong>Methods:</strong> This was an analysis of the PIVENS and FLINT trials in adults with NASH who had liver biopsies at baseline and at either 1.5 years or 2 years. Multivariable regression models examined how weight change was associated with changes in (a) blood liver markers, (b) NASH resolution with no fibrosis worsening, (c) fibrosis improving with no NASH worsening, and (d) individual histological features.</p> <p><strong>Results:</strong> The BMI of the 421 participants was 34.4kg/m2 (SD:6.5) and their mean weight change was +0.4kg (SD:6.5). Weight change was independently and positively associated with changes in liver enzymes and the Fibrosis-4 score (all p<0.001). Each kg of weight loss was associated with 7% (95%CI: 3-10%, p<0.001) increase in odds of achieving NASH resolution with no fibrosis worsening and with 5% (95%CI: 1%-8%, p=0.01) increase in odds of achieving fibrosis improvement with no NASH worsening. Weight gain was associated with worsening of disease activity. For every kg of weight lost, the odds of fibrosis improving were 5% (95%CI: 2-8%, p=0.001). There was no evidence that the association between weight change and outcome depended upon pharmacological treatment, trial, body mass index, and baseline fibrosis.</p> <p><strong>Conclusions:</strong> Weight change was independently and monotonically associated with changes in biochemical and histological features of NASH. Guidelines for NASH management should incorporate recommendations for both avoidance of weight gain and support to lose weight.</p>
Parents’ concerns and beliefs about temperature measurement in children: a qualitative study
© 2021, The Author(s). Background: Nearly 40% of parents with children aged 6 to 17 months consult a healthcare professional when their child has a high temperature. Clinical guidelines recommend temperature measurement in these children, but little is known about parents’ experiences of and beliefs about temperature measurement. This study aimed to explore parents’ concerns and beliefs about temperature measurement in children. Methods: Semi-structured qualitative interviews were conducted from May 2017 to June 2018 with 21 parents of children aged 4 months to 5.5 years, who were purposively sampled from the METRIC study (a method comparison study comparing non-contact infrared thermometers to axillary and tympanic thermometers in acutely ill children). Data analysis followed a thematic approach. Results: Parents described the importance of being able to detect fever, in particular high fevers, and how this then influenced their actions. The concept of “accuracy” was valued by parents but the aspects of performance which were felt to reflect accuracy varied. Parents used numerical values of temperature in four main ways: determining precision of the thermometer on repeat measures, detecting a “bad” fever, as an indication to administer antipyretics, or monitoring response to treatment. Family and social networks, the internet, and medical professionals and resources, were all key sources of advice for parents regarding fever, and guiding thermometer choice. Conclusions: Temperature measurement in children has diagnostic value but can either empower, or cause anxiety and practical challenges for parents. This represents an opportunity for both improved communication between parents and healthcare professionals, and technological development, to support parents to manage febrile illness with greater confidence in the home.
The contribution of the acute phase response to the pathogenesis of relapse in chronic-relapsing experimental autoimmune encephalitis models of multiple sclerosis
© 2017 The Author(s). Background: Increased relapse rates in multiple sclerosis (MS) as a consequence of peripheral immune system activation, owing to infection for example, have been widely reported, but the mechanism remains unclear. Acute brain injury models can be exacerbated by augmenting the hepatic acute phase response (APR). Here, we explored the contribution of the hepatic APR to relapse in two rodent models of MS. Methods: Mice with MOG-CFA-induced chronic relapsing experimental autoimmune encephalitis (CR-EAE) were killed before, during and after the first phase of disease, and the brain and liver chemokine, cytokine and acute phase protein (APP) mRNA expression profile was determined. During remission, the APR was reactivated with an intraperitoneal lipopolysaccharide (LPS) and clinical score was monitored throughout. To explore the downstream mediators, CXCL-1, which is induced as part of the APR, was injected into animals with a focal, cytokine/MOG-induced EAE lesion (fEAE) and the cellularity of the lesions was assessed. Results: Compared to CFA control, in a rodent CR-EAE model, an hepatic APR preceded clinical signs and central cytokine production in the initial phase of disease. Compared to administration in naïve animals, an LPS challenge during the asymptomatic remission phase of CR-EAE rodents provoked relapse and resulted in the increased and extended expression of specific peripheral hepatic chemokines. CXCL-1 and several other APPs were markedly elevated. A single intravenous administration of the highly induced chemokine, CXCL-1, was found to be sufficient to reactivate the lesions by increasing microglial activation and the recruitment of T cells in fEAE lesions. Conclusions: The APR plays a contributing role to the pathology seen in models of chronic brain injury and in translating the effects of peripheral immune system stimulation secondary to trauma or infection into central pathology and behavioural signs. Further elucidation of the exact mechanisms in this process will inform development of more effective, selective therapies in MS that, by suppressing the hepatic chemokine response, may prevent relapse.
The contribution of the acute phase response to the pathogenesis of relapse in chronic-relapsing experimental autoimmune encephalitis models of multiple sclerosis.
BACKGROUND: Increased relapse rates in multiple sclerosis (MS) as a consequence of peripheral immune system activation, owing to infection for example, have been widely reported, but the mechanism remains unclear. Acute brain injury models can be exacerbated by augmenting the hepatic acute phase response (APR). Here, we explored the contribution of the hepatic APR to relapse in two rodent models of MS. METHODS: Mice with MOG-CFA-induced chronic relapsing experimental autoimmune encephalitis (CR-EAE) were killed before, during and after the first phase of disease, and the brain and liver chemokine, cytokine and acute phase protein (APP) mRNA expression profile was determined. During remission, the APR was reactivated with an intraperitoneal lipopolysaccharide (LPS) and clinical score was monitored throughout. To explore the downstream mediators, CXCL-1, which is induced as part of the APR, was injected into animals with a focal, cytokine/MOG-induced EAE lesion (fEAE) and the cellularity of the lesions was assessed. RESULTS: Compared to CFA control, in a rodent CR-EAE model, an hepatic APR preceded clinical signs and central cytokine production in the initial phase of disease. Compared to administration in naïve animals, an LPS challenge during the asymptomatic remission phase of CR-EAE rodents provoked relapse and resulted in the increased and extended expression of specific peripheral hepatic chemokines. CXCL-1 and several other APPs were markedly elevated. A single intravenous administration of the highly induced chemokine, CXCL-1, was found to be sufficient to reactivate the lesions by increasing microglial activation and the recruitment of T cells in fEAE lesions. CONCLUSIONS: The APR plays a contributing role to the pathology seen in models of chronic brain injury and in translating the effects of peripheral immune system stimulation secondary to trauma or infection into central pathology and behavioural signs. Further elucidation of the exact mechanisms in this process will inform development of more effective, selective therapies in MS that, by suppressing the hepatic chemokine response, may prevent relapse.
CSF tau and the CSF tau/ABeta ratio for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI)
© 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the diagnostic accuracy of 1) CSF tau, 2) CSF p-tau, 3) the CSF tau/ABeta ratio and 4) the CSF p-tau/ABeta ratio index tests at various thresholds for detecting participants with mild cognitive impairment (MCI) at baseline who would clinically convert to Alzheimer's disease or other forms of dementia at follow-up. To investigate the amount of and associations of heterogeneity in the included studies of test accuracy. We expect that heterogeneity will be likely and that it will be an important component of the review. The potential sources of heterogeneity, which will be used as a framework for the investigation of heterogeneity, include target population, index test, target disorder and study quality.
Erratum: The role of PPAR activation during the systemic response to brain injury. [Journal of Neuroinflammation. 12, (2015) (99)] DOI: 10.1186/s12974-015-0295-7
© The Author(s). Upon publication of the original article [1], it was noticed that the author's name "Borna Guevel" was incorrectly spelt as "Borna Geuvel". This has now been corrected in this erratum.
The role of PPAR activation during the systemic response to brain injury
© 2015 Losey et al.; licensee BioMed Central. Background: Fenofibrate, a PPAR-α activator, has shown promising results as a neuroprotective therapy, with proposed anti-inflammatory and anti-oxidant effects. However, it displays poor blood-brain barrier permeability leading to some ambiguity over its mechanism of action. Experimentally induced brain injury has been shown to elicit a hepatic acute phase response that modulates leukocyte recruitment to the injured brain. Here, we sought to discover whether one effect of fenofibrate might include the suppression of the acute phase response (APR) following brain injury. Methods: A 1-h intraluminal thread middle cerebral artery occlusion (MCAO) model followed by a 6-h reperfusion was performed in C57/BL6 mice. Quantitative reverse transcriptase-polymerase chain reaction was then used to measure hepatic expression of chemokine (C-X-C motif) ligand 1 (CXCL1), chemokine ligand 10 (CXCL10) and serum amyloid A-1 (SAA-1), and immunohistochemical analysis was used to quantify brain and hepatic neutrophil infiltration following stroke. Results: The MCAO and sham surgery induced the expression of all three acute phase reactants. A 14-day fenofibrate pre-treatment decreased reactant production, infarct volume, and neutrophil recruitment to the brain and liver, which is a hallmark of the APR. Conclusions: The data highlight a novel mechanism of action for fenofibrate and lend further evidence towards the promotion of its use as a prophylactic therapy in patients at risk of cerebral ischaemia. Further research is required to elucidate the mechanistic explanation underlying its actions.
CSF tau and the CSF tau/ABeta ratio for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI)
© 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Background: Research suggests that measurable change in cerebrospinal fluid (CSF) biomarkers occurs years in advance of the onset of clinical symptoms (Beckett 2010). In this review, we aimed to assess the ability of CSF tau biomarkers (t-tau and p-tau) and the CSF tau (t-tau or p-tau)/ABeta ratio to enable the detection of Alzheimer's disease pathology in patients with mild cognitive impairment (MCI). These biomarkers have been proposed as important in new criteria for Alzheimer's disease dementia that incorporate biomarker abnormalities. Objectives: To determine the diagnostic accuracy of 1) CSF t-tau, 2) CSF p-tau, 3) the CSF t-tau/ABeta ratio and 4) the CSF p-tau/ABeta ratio index tests for detecting people with MCI at baseline who would clinically convert to Alzheimer's disease dementia or other forms of dementia at follow-up. Search methods: The most recent search for this review was performed in January 2013. We searched MEDLINE (OvidSP), Embase (OvidSP), BIOSIS Previews (Thomson Reuters Web of Science), Web of Science Core Collection, including Conference Proceedings Citation Index (Thomson Reuters Web of Science), PsycINFO (OvidSP), and LILACS (BIREME). We searched specialized sources of diagnostic test accuracy studies and reviews. We checked reference lists of relevant studies and reviews for additional studies. We contacted researchers for possible relevant but unpublished data. We did not apply any language or data restriction to the electronic searches. We did not use any methodological filters as a method to restrict the search overall. Selection criteria: We selected those studies that had prospectively well-defined cohorts with any accepted definition of MCI and with CSF t-tau or p-tau and CSF tau (t-tau or p-tau)/ABeta ratio values, documented at or around the time the MCI diagnosis was made. We also included studies which looked at data from those cohorts retrospectively, and which contained sufficient data to construct two by two tables expressing those biomarker results by disease status. Moreover, studies were only selected if they applied a reference standard for Alzheimer's disease dementia diagnosis, for example, the NINCDS-ADRDA or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Data collection and analysis: We screened all titles generated by the electronic database searches. Two review authors independently assessed the abstracts of all potentially relevant studies, and the full papers for eligibility. Two independent assessors performed data extraction and quality assessment. Where data allowed, we derived estimates of sensitivity at fixed values of specificity from the model we fitted to produce the summary receiver operating characteristic (ROC) curve. Main results: In total, 1282 participants with MCI at baseline were identified in the 15 included studies of which 1172 had analysable data; 430 participants converted to Alzheimer's disease dementia and 130 participants to other forms of dementia. Follow-up ranged from less than one year to over four years for some participants, but in the majority of studies was in the range one to three years. Conversion to Alzheimer's disease dementia The accuracy of the CSF t-tau was evaluated in seven studies (291 cases and 418 non-cases).The sensitivity values ranged from 51% to 90% while the specificity values ranged from 48% to 88%. At the median specificity of 72%, the estimated sensitivity was 75% (95% CI 67 to 85), the positive likelihood ratio was 2.72 (95% CI 2.43 to 3.04), and the negative likelihood ratio was 0.32 (95% CI 0.22 to 0.47). Six studies (164 cases and 328 non-cases) evaluated the accuracy of the CSF p-tau. The sensitivities were between 40% and 100% while the specificities were between 22% and 86%. At the median specificity of 47.5%, the estimated sensitivity was 81% (95% CI: 64 to 91), the positive likelihood ratio was 1.55 (CI 1.31 to 1.84), and the negative likelihood ratio was 0.39 (CI: 0.19 to 0.82). Five studies (140 cases and 293 non-cases) evaluated the accuracy of the CSF p-tau/ABeta ratio. The sensitivities were between 80% and 96% while the specificities were between 33% and 95%. We did not conduct a meta-analysis because the studies were few and small. Only one study reported the accuracy of CSF t-tau/ABeta ratio. Our findings are based on studies with poor reporting. A significant number of studies had unclear risk of bias for the reference standard, participant selection and flow and timing domains. According to the assessment of index test domain, eight of 15 studies were of poor methodological quality. The accuracy of these CSF biomarkers for 'other dementias' had not been investigated in the included primary studies. Investigation of heterogeneity The main sources of heterogeneity were thought likely to be reference standards used for the target disorders, sources of recruitment, participant sampling, index test methodology and aspects of study quality (particularly, inadequate blinding). We were not able to formally assess the effect of each potential source of heterogeneity as planned, due to the small number of studies available to be included. Authors' conclusions: The insufficiency and heterogeneity of research to date primarily leads to a state of uncertainty regarding the value of CSF testing of t-tau, p-tau or p-tau/ABeta ratio for the diagnosis of Alzheimer's disease in current clinical practice. Particular attention should be paid to the risk of misdiagnosis and overdiagnosis of dementia (and therefore over-treatment) in clinical practice. These tests, like other biomarker tests which have been subject to Cochrane DTA reviews, appear to have better sensitivity than specificity and therefore might have greater utility in ruling out Alzheimer's disease as the aetiology to the individual's evident cognitive impairment, as opposed to ruling it in. The heterogeneity observed in the few studies awaiting classification suggests our initial summary will remain valid. However, these tests may have limited clinical value until uncertainties have been addressed. Future studies with more uniformed approaches to thresholds, analysis and study conduct may provide a more homogenous estimate than the one that has been available from the included studies we have identified.