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Neutralising antibody potency against SARS-CoV-2 wild-type and omicron BA.1 and BA.4/5 variants in patients with inflammatory bowel disease treated with infliximab and vedolizumab after three doses of COVID-19 vaccine (CLARITY IBD): an analysis of a prospective multicentre cohort study
No full textBACKGROUND: Anti-TNF drugs, such as infliximab, are associated with attenuated antibody responses after SARS-CoV-2 vaccination. We aimed to determine how the anti-TNF drug infliximab and the anti-integrin drug vedolizumab affect vaccine-induced neutralising antibodies against highly transmissible omicron (B.1.1.529) BA.1, and BA.4 and BA.5 (hereafter BA.4/5) SARS-CoV-2 variants, which possess the ability to evade host immunity and, together with emerging sublineages, are now the dominating variants causing current waves of infection. METHODS: CLARITY IBD is a prospective, multicentre, observational cohort study investigating the effect of infliximab and vedolizumab on SARS-CoV-2 infection and vaccination in patients with inflammatory bowel disease (IBD). Patients aged 5 years and older with a diagnosis of IBD and being treated with infliximab or vedolizumab for 6 weeks or longer were recruited from infusion units at 92 hospitals in the UK. In this analysis, we included participants who had received uninterrupted biological therapy since recruitment and without a previous SARS-CoV-2 infection. The primary outcome was neutralising antibody responses against SARS-CoV-2 wild-type and omicron subvariants BA.1 and BA.4/5 after three doses of SARS-CoV-2 vaccine. We constructed Cox proportional hazards models to investigate the risk of breakthrough infection in relation to neutralising antibody titres. The study is registered with the ISRCTN registry, ISRCTN45176516, and is closed to accrual. FINDINGS: Between Sept 22 and Dec 23, 2020, 7224 patients with IBD were recruited to the CLARITY IBD study, of whom 1288 had no previous SARS-CoV-2 infection after three doses of SARS-CoV-2 vaccine and were established on either infliximab (n=871) or vedolizumab (n=417) and included in this study (median age was 46·1 years [IQR 33·6-58·2], 610 [47·4%] were female, 671 [52·1%] were male, 1209 [93·9%] were White, and 46 [3·6%] were Asian). After three doses of SARS-CoV-2 vaccine, 50% neutralising titres (NT50s) were significantly lower in patients treated with infliximab than in those treated with vedolizumab, against wild-type (geometric mean 2062 [95% CI 1720-2473] vs 3440 [2939-4026]; p<0·0001), BA.1 (107·3 [86·40-133·2] vs 648·9 [523·5-804·5]; p<0·0001), and BA.4/5 (40·63 [31·99-51·60] vs 223·0 [183·1-271·4]; p<0·0001) variants. Breakthrough infection was significantly more frequent in patients treated with infliximab (119 [13·7%; 95% CI 11·5-16·2] of 871) than in those treated with vedolizumab (29 [7·0% [4·8-10·0] of 417; p=0·00040). Cox proportional hazards models of time to breakthrough infection after the third dose of vaccine showed infliximab treatment to be associated with a higher hazard risk than treatment with vedolizumab (hazard ratio [HR] 1·71 [95% CI 1·08-2·71]; p=0·022). Among participants who had a breakthrough infection, we found that higher neutralising antibody titres against BA.4/5 were associated with a lower hazard risk and, hence, a longer time to breakthrough infection (HR 0·87 [0·79-0·95]; p=0·0028). INTERPRETATION: Our findings underline the importance of continued SARS-CoV-2 vaccination programmes, including second-generation bivalent vaccines, especially in patient subgroups where vaccine immunogenicity and efficacy might be reduced, such as those on anti-TNF therapies. FUNDING: Royal Devon University Healthcare NHS Foundation Trust; Hull University Teaching Hospital NHS Trust; NIHR Imperial Biomedical Research Centre; Crohn's and Colitis UK; Guts UK; National Core Studies Immunity Programme, UK Research and Innovation; and unrestricted educational grants from F Hoffmann-La Roche, Biogen, Celltrion Healthcare, Takeda, and Galapagos.Published version, accepted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
Clinical management of high-output stoma: a systematic literature review and meta-analysis
No full textPURPOSE: High output is a common complication after stoma formation. Although the management of high output is described in the literature, there is a lack of consensus on definitions and treatment. Our aim was to review and summarise the current best evidence. METHODS: MEDLINE, Cochrane Library, BNI, CINAHL, EMBASE, EMCARE, and ClinicalTrials.gov were searched from 1 Jan 2000 to 31 Dec 2021 for relevant articles on adult patients with a high-output stoma. Patients with enteroatmospheric fistulas and case series/reports were excluded. Risk of bias was assessed using RoB2 and MINORS. The review was registered in PROSPERO (CRD42021226621). RESULTS: The search strategy identified 1095 articles, of which 32 studies with 768 patients met the inclusion criteria. These studies comprised 15 randomised controlled trials, 13 non-randomised prospective trials, and 4 retrospective cohort studies. Eighteen different interventions were assessed. In the meta-analysis, there was no difference in stoma output between controls and somatostatin analogues (g - 1.72, 95% CI - 4.09 to 0.65, p = 0.11, I(2) = 88%, t(2) = 3.09), loperamide (g - 0.34, 95% CI - 0.69 to 0.01, p = 0.05, I(2) = 0%, t(2) = 0) and omeprazole (g - 0.31, 95% CI - 2.46 to 1.84, p = 0.32, I(2) = 0%, t(2) = 0). Thirteen randomised trials showed high concern of bias, one some concern, and one low concern. The non-randomised/retrospective trials had a median MINORS score of 12 out of 24 (range 7-17). CONCLUSION: There is limited high-quality evidence favouring any specific widely used drug over the others in the management of high-output stoma. Evidence, however, is weak due to inconsistent definitions, risk of bias and poor methodology in the existing studies. We recommend the development of validated core descriptor and outcomes sets, as well as patient-reported outcome measures.unknownThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
From haematuria to nephroureterectomy via urine cytology-A case study
No full textPublished version, accepted version (12 month embargo)RD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Appropriateness of two-week wait head and neck cancer referrals to a district general hospital
No full textObjectives The NHS advise urgent referral of patients with suspected head and neck cancers to secondary care to be seen via a two-week wait pathway. The objective of this review was to analyse the two-week wait head and neck cancer referrals to a district general hospital and to identify the prevalence of oral cancer.Materials and methods Patients referred via an urgent two-week wait cancer pathway during the period of 12 October 2020 to 19 January 2022 were identified. Data were extracted and analysed for referral source, patient sex, whether or not a biopsy was undertaken, and the number of patients with a final positive cancer diagnosis.Results Overall, 883 two-week wait referrals were received. Most referrals came from general medical practitioners (50%) followed by general dental practitioners (37%). A total of 379 patients (46%) underwent a biopsy, special investigations, or internal referral to another speciality. The overall prevalence of cancer was 6.2%. Most referrals received were for commonly occurring benign conditions.Conclusion Despite many two-week wait suspected cancer referrals, only a small percentage of patients go on to be diagnosed with head and neck cancer. These results highlight the number of avoidable referrals, which ultimately impact patient waiting lists and clinician time.Published version, accepted version (6 month embargo)Full Text unavailable for 1 year from time of publication
A simple formula to control posterior tibial slope during proximal tibial osteotomies
No full textBACKGROUND: High tibial osteotomy surgery is a widely successful joint-preserving procedure which alters the hip-knee-ankle axis which can delay the progression of osteoarthritis; however, conventional osteotomy surgical procedures do not adequately control the posterior tibial slope. This study aimed to determine the key variables influencing posterior tibial slope during high tibial osteotomy and provide a simple means of implementing the findings during pre-operative planning. METHODS: A virtual cohort of twenty-eight proximal tibia geometries of knee osteoarthritis patients was used in the study. Firstly, absolute posterior tibial slope values were contrasted using anatomical and posterior mechanical axis measurement approaches. Secondly, the influence of variables affecting posterior tibial slope change during osteotomy surgery was investigated using 3D preoperative planning surgical simulation and analytical modelling. FINDINGS: There was a poor correlation (R(2) = 0.38) between the different clinical measurements of posterior tibial slope; with an average of 7.0 ± 1.3° and 14.8 ± 2.2° respectively. An analytical solution for the change in posterior tibial slope was derived based on the hinge axis angle and the osteotomy opening angle. For three different opening angles (6°, 9° and 12°) and seven different hinge axis orientations (-30° to +30°), the results obtained were identical for the analytical model and the 3D preoperative planning. INTERPRETATION: This study determined that the key variables affecting posterior tibial slope during high tibial osteotomy are the osteotomy opening angle and the hinge axis orientation. The derived formula provides a simple means of determining the change in posterior tibial slope resulting from a particular surgical approach.Published version, accepted version (12 month embargo)Not hel
The Royal College of Ophthalmologists' National Ophthalmology Database Study of Cataract Surgery: Report 12, Risk factors for suprachoroidal haemorrhage during cataract surgery
No full textOBJECTIVE: To establish the incidence of acute intraoperative suprachoroidal haemorrhage (AISH) during cataract surgery and identify the risk factors for this complication. METHODS: Data from the Royal College of Ophthalmologists' National Ophthalmology Database was analysed. During the 11-year study period, from 01/04/2010 to 31/03/2021, 709 083 operations performed on 498 170 patients from 65 centres were eligible for inclusion. RESULTS: AISH occurred in 0.03% (204/709 083, approximately 1 in 3 500) of eligible cataract operations performed during the study period. Posterior capsule rupture was the risk factor most strongly associated with AISH (OR: 17.6, 95% CI: 12.4-24.9, p < 0.001). Other ocular risk factors identified were raised intraocular pressure (IOP) preoperatively (OR: 3.7, 95% CI: 2.5-5.5, p < 0.001), glaucoma (OR: 1.7, 95% CI: 1.2-2.4, p = 0.004). Risk increased with age and patients aged over 90 years were at greatest risk (OR: 6.7, 95% CI: 3.5-12.8, p < 0.001). The addition of intracameral anaesthetic when performing surgery under topical anaesthetic appears to be protective (OR: 0.5, 95% CI: 0.3-0.8, p = 0.003), compared to topical anaesthetic alone. There was a 16-fold increase in the incidence of vision loss when AISH occurred. CONCLUSIONS: The risk of AISH during modern cataract surgery is approximately 1 in 3 500 and is associated with a significant increase in the risk of vision loss should it occur. Posterior capsule rupture is the risk factor most strongly associated with AISH. Preoperative IOP control is a modifiable risk factor. The use of intracameral anaesthesia may reduce the risk of AISH.Accepted version (6 month embargo), submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
Disease-modifying therapies and features linked to treatment response in type 1 diabetes prevention: a systematic review
No full textBACKGROUND: Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Prevention efforts have focused on immune modulation and supporting beta cell health before or around diagnosis; however, heterogeneity in disease progression and therapy response has limited translation to clinical practice, highlighting the need for precision medicine approaches to T1D disease modification. METHODS: To understand the state of knowledge in this area, we performed a systematic review of randomized-controlled trials with ≥50 participants cataloged in PubMed or Embase from the past 25 years testing T1D disease-modifying therapies and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument. RESULTS: We identify and summarize 75 manuscripts, 15 describing 11 prevention trials for individuals with increased risk for T1D, and 60 describing treatments aimed at preventing beta cell loss at disease onset. Seventeen interventions, mostly immunotherapies, show benefit compared to placebo (only two prior to T1D onset). Fifty-seven studies employ precision analyses to assess features linked to treatment response. Age, beta cell function measures, and immune phenotypes are most frequently tested. However, analyses are typically not prespecified, with inconsistent methods of reporting, and tend to report positive findings. CONCLUSIONS: While the quality of prevention and intervention trials is overall high, the low quality of precision analyses makes it difficult to draw meaningful conclusions that inform clinical practice. To facilitate precision medicine approaches to T1D prevention, considerations for future precision studies include the incorporation of uniform outcome measures, reproducible biomarkers, and prespecified, fully powered precision analyses into future trial design.
Type 1 diabetes (T1D) is a condition that results from the destruction of a type of cell in the pancreas that produces the hormone insulin, leading to lifelong dependence on insulin injections. T1D prevention remains a challenging goal, largely due to the immense variability in disease processes and progression. Therapies tested to date in medical research settings (clinical trials) work only in a subset of individuals, highlighting the need for more tailored prevention approaches. We reviewed clinical trials of therapies targeting the disease process in T1D. While the overall quality of trials was high, studies testing individual features affecting responses to treatments were low. This review reveals an important need to carefully plan high-quality analyses of features that affect treatment response in T1D, to ensure that tailored approaches may one day be applied to clinical practice.
eng MJH Life Sciences and as a consultant for DRI Healthcare. C.E.M. reported serving on advisory boards for Provention Bio, Isla Technologies, MaiCell Technologies, Avotres, DiogenyX, and Neurodon; receiving in-kind research support from Bristol Myers Squibb and Nimbus Pharmaceuticals; and receiving investigator-initiated grants from Lilly Pharmaceuticals and Astellas Pharmaceuticals. L.A.D. reports research support to institutions from Dompe, Lilly, Mannkind, Provention, Zealand, and consulting relationships with Abata and Vertex. R.A.O. had a UK MRC Confidence in concept grant to develop a T1D GRS biochip with Randox Ltd and has ongoing research funding from Randox R & D. No other authors report any relevant conflicts of interest.Published version, submitted versionRDUH can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Editor's choice-December 2023
No full textAccepted version (12 month embargo)RD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
The Association of Coloproctology of Great Britain and Ireland guideline on the management of anal fissure
No full textAIM: The management of anal fissure: ACPGBI position statement was written 15 years ago. [KLR Cross et al., Colorectal Dis, 2008]. Our aim was to update the guideline and provide recommendations on the most effective treatment for patients with anal fissures utilising a multidisciplinary, rigorous guideline methodology. METHODS: The development process consisted of six phases. In phase 1 we defined the scope of the guideline. The patient population included patients with acute and chronic anal fissure. The target group was all practitioners (primary and secondary care) treating patients with fissures and, in addition, healthcare workers and patients who desired information regarding fissure management. In phase 2 we formed a guideline development group (GDG) including a methodologist. In phase 3 review questions were formulated, using a reversed PICO process, starting with possible recommendations based on the GDG's knowledge. In phase 4 a comprehensive literature search focused on existing systematic reviews addressing each review question, supplemented by more recent studies if appropriate. In phase 5 data were extracted from the included papers and checked by the GDG. If indicated, meta-analysis of systematic review data was updated by the GDG. During phase 6 the GDG members decided what recommendations could be made based on the evidence in the literature and strength of the recommendation was assessed using 'grade'. RESULTS: This guideline is divided into two sections: Primary care which includes (i) diagnosis; (ii) basic treatment; (iii) topical treatment; and secondary care which includes (iv) botulinum toxin therapy; (v) surgical intervention and (vi) special situations (including pregnancy and breast-feeding patients, children, receptive anal intercourse and low-pressure fissures). A total of 23 recommendations were formulated. A new term clinically healed was described by the GDG. CONCLUSION: This guideline provides an up-to-date evidence-based summary of the current knowledge of the management of anal fissure and may serve as a useful guide for clinicians as well as a potential reference for patients.Accepted version (12 month embargo)RD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Mastitis and Mammary Abscess Management Audit (MAMMA) in the UK and Ireland
No full textBACKGROUND: The aim of this multicentre prospective audit was to describe the current practice in the management of mastitis and breast abscesses in the UK and Ireland, with a specific focus on rates of surgical intervention. METHODS: This audit was conducted in two phases from August 2020 to August 2021; a phase 1 practice survey and a phase 2 prospective audit. Primary outcome measurements for phase 2 included patient management pathway characteristics and treatment type (medical/radiological/surgical). RESULTS: A total of 69 hospitals participated in phase 2 (1312 patients). The key findings were a high overall rate of incision and drainage (21.0 per cent) and a lower than anticipated proportion of ultrasound-guided aspiration of breast abscesses (61.0 per cent). Significant variations were observed regarding the rate of incision and drainage (range 0-100 per cent; P < 0.001) and the rate of needle aspiration (range 12.5-100 per cent; P < 0.001) between individual units. Overall, 22.5 per cent of patients were admitted for inpatient treatment, out of whom which 72.9 per cent were commenced on intravenous antibiotics. The odds of undergoing incision and drainage for a breast abscess or being admitted for inpatient treatment were significantly higher if patients presented at the weekend compared with a weekday (P ≤ 0.023). Breast specialists reviewed 40.9 per cent of all patients directly, despite the majority of patients (74.2 per cent) presenting within working hours on weekdays. CONCLUSIONS: Variation in practice exists in the management of mastitis and breast abscesses, with high rates of incision and drainage in certain regions of the UK. There is an urgent need for a national best-practice toolbox to minimize practice variation and standardize patient care.
Mastitis and breast abscess is a painful infection of the breast. It is an extremely common breast problem. One in three women can get this condition at some stage in their life. To treat a breast abscess, the pus inside should be drained out of the body. This can be done either by cutting into the breast using surgery or by inserting a fine needle using an ultrasonography scan (which uses ultrasound). Fine-needle drainage has the benefit that it does not require admission to hospital. Surgery can cause the breast to look misshapen. It is unknown which method is used more often in the UK and Ireland. The aim of this study was to describe how mastitis and breast abscesses are treated in the UK and Ireland. This study involved a survey of practice (phase 1) and collection of data, which are routinely recorded for these patients (phase 2). This study involved 69 hospitals and 1312 patient records. One in five women had an operation for a breast abscess. This was higher than expected. Six in 10 women had a pus drainage using a fine needle. The chance of having an operation depended on the hospital. Women that came to hospital at the weekend were almost twice as likely to have an operation. One in five women were admitted to hospital. The chances of that more than doubled if a woman came to hospital at the weekend. There are differences in treatment of mastitis and breast abscesses across the UK and Ireland. Changes need to be put in place to make access to treatment more equal.
engPublished version, accepted version (12 month embargo), submitted versionRD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted