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An MRI study demonstrating consistent anatomic relation of central longitudinal artery and associated periosteal vessels with the medial femoral epicondyle and adductor tubercle-A visual landmark method for femoral tunnel placement in medial patellofemoral ligament reconstruction
No full textThe two most common techniques to determine femoral tunnel placement during medial patellofemoral ligament (MPFL) reconstruction are radiographic and by palpation. Their intra/interobserver reliability is widely debated. Both techniques rely on identifying bony landmarks such as the medial epicondyle (ME) and adductor tubercle (AT) during surgery. During MPFL reconstructive surgery, the central longitudinal vessels (CLVs) are seen consistently. The aim of this study was to investigate the anatomic relationship of CLV to ME and AT and to determine if CLV might be used as a landmark during MPFL reconstruction. A retrospective review of MRI scans in skeletally mature patients was undertake. There were two groups, a PFI group that consisted of patients with a diagnosis of patellofemoral instabiliy (PFI) and a non-PFI group that underwent MRI scan for an alternative diagnosis. MRIs were measured for the CLV-ME-AT anatomy and relationship. Following exclusions, 50 patients were identified in each group. The CLV passed anterior to the AT and ME in all patients. ME morphology did not differ greatly between the groups except in the tubercle height, where there was statistically significant but not a clinically important difference (larger in the non-PFI group, 2.95 vs. 2.52 mm, p = 0.002). The CLV to ME tip distance was consistent between the groups (PFI group 3.8 mm and non-PFI group 3.9 mm). The CLV-ME-AT relationship remained consistent irrespective of patients' presenting pathology. The CLV consistently courses anterior to ME and AT. The CLV could be used as a vascular landmark assisting femoral tunnel placement during MPFL reconstruction.Published version, accepted version (12 month embargo), submitted versionNot hel
A Golden Hour and Golden Opportunity for ß-Cell Preservation
No full textAccepted version, submitted versionJournal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridioides difficile infection and other potential indications: second edition of joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines
No full textThe first British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS)-endorsed faecal microbiota transplant (FMT) guidelines were published in 2018. Over the past 5 years, there has been considerable growth in the evidence base (including publication of outcomes from large national FMT registries), necessitating an updated critical review of the literature and a second edition of the BSG/HIS FMT guidelines. These have been produced in accordance with National Institute for Health and Care Excellence-accredited methodology, thus have particular relevance for UK-based clinicians, but are intended to be of pertinence internationally. This second edition of the guidelines have been divided into recommendations, good practice points and recommendations against certain practices. With respect to FMT for Clostridioides difficile infection (CDI), key focus areas centred around timing of administration, increasing clinical experience of encapsulated FMT preparations and optimising donor screening. The latter topic is of particular relevance given the COVID-19 pandemic, and cases of patient morbidity and mortality resulting from FMT-related pathogen transmission. The guidelines also considered emergent literature on the use of FMT in non-CDI settings (including both gastrointestinal and non-gastrointestinal indications), reviewing relevant randomised controlled trials. Recommendations are provided regarding special areas (including compassionate FMT use), and considerations regarding the evolving landscape of FMT and microbiome therapeutics.Published version, accepted version, submitted versionJournal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
The impact of inversions across 33,924 families with rare disease from a national genome sequencing project
No full textDetection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (>50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts.Published version, accepted version (6 month embargo), submitted versionJournal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Acute monocular visual loss: time to call the stroke team?
No full textA man in his 90s presented with acute monocular loss of vision; the emergency department triage alerted the stroke team. He underwent urgent parallel assessments by the stroke and ophthalmology teams and was diagnosed with central retinal artery occlusion. The ultimate decision was made to manage him conservatively, rather than with intravenous thrombolysis, and his visual function has remained poor. We discuss the current evidence for using intravenous thrombolysis in people with central retinal artery occlusion and use this case to exemplify the practical issues that must be overcome if ongoing randomised clinical trials of central retinal artery occlusion confirm a definite benefit from using intravenous thrombolysis.0RDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM
No full textCryptococcosis is a major worldwide disseminated invasive fungal infection. Cryptococcosis, particularly in its most lethal manifestation of cryptococcal meningitis, accounts for substantial mortality and morbidity. The breadth of the clinical cryptococcosis syndromes, the different patient types at-risk and affected, and the vastly disparate resource settings where clinicians practice pose a complex array of challenges. Expert contributors from diverse regions of the world have collated data, reviewed the evidence, and provided insightful guideline recommendations for health practitioners across the globe. This guideline offers updated practical guidance and implementable recommendations on the clinical approaches, screening, diagnosis, management, and follow-up care of a patient with cryptococcosis and serves as a comprehensive synthesis of current evidence on cryptococcosis. This Review seeks to facilitate optimal clinical decision making on cryptococcosis and addresses the myriad of clinical complications by incorporating data from historical and contemporary clinical trials. This guideline is grounded on a set of core management principles, while acknowledging the practical challenges of antifungal access and resource limitations faced by many clinicians and patients. More than 70 societies internationally have endorsed the content, structure, evidence, recommendation, and pragmatic wisdom of this global cryptococcosis guideline to inform clinicians about the past, present, and future of care for a patient with cryptococcosis.Published version, accepted version (12 months embrago)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
Use of immunomodulators in combination with infliximab in Crohn's disease: time for a reappraisal?
No full textPublished version, accepted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial
No full textBACKGROUND: Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies. METHODS: PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index =7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI =5) plus raised inflammatory markers (CRP >upper limit of normal or faecal calprotectin =200 µg/g, or both), while remission was the converse-ie, quiescent symptoms (HBI <5) or resolved inflammatory markers (both CRP = the upper limit of normal and calprotectin <200 µg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228). FINDINGS: Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0-191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker-treatment interaction effect (absolute difference 1 percentage points, 95% CI -15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p<0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight). INTERPRETATION: Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease. FUNDING: Wellcome and PredictImmune Ltd.Published version, accepted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
Effect of parental touch on relieving acute procedural pain in neonates and parental anxiety (Petal): a multicentre, randomised controlled trial in the UK
No full textBACKGROUND: Touch interventions such as massage and skin-to-skin contact relieve neonatal pain. The Parental touch trial (Petal) aimed to assess whether parental stroking of their baby before a clinically required heel lance, at a speed of approximately 3 cm/s to optimally activate C-tactile nerve fibres, provides effective pain relief. METHODS: Petal is a multicentre, randomised, parallel-group interventional superiority trial conducted in the John Radcliffe Hospital (Oxford University Hospitals NHS Foundation Trust, Oxford, UK) and the Royal Devon and Exeter Hospital (Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK). Neonates without neurological abnormalities who were born at 35 weeks gestational age or more and required a blood test via a heel lance in the first week of life were randomly assigned (1:1) to receive parental touch for 10 s either before (intervention group) or after (control group) the clinically required heel lance. Randomisation was managed at the Oxford site using a web-based minimisation algorithm with allocation concealment. The primary outcome measure was the magnitude of noxious-evoked brain activity in response to the heel lance measured with electroencephalography (EEG). Secondary outcome measures were Premature Infant Pain Profile-Revised (PIPP-R) score, development of tachycardia, and parental anxiety score. For all outcomes, the per-protocol effect was estimated via complier average causal effect analysis on the full analysis set. The trial is registered on ISRCTN (ISRCTN14135962) and ClinicalTrials.gov (NCT04901611). FINDINGS: Between Sept 1, 2021, and Feb 7, 2023, 159 parents were approached to participate in the study, and 112 neonates were included. 56 neonates were randomly assigned to the intervention group of parental stroking before the heel lance and 56 to the control group of parental stroking after the heel lance. The mean of the magnitude of the heel lance-evoked brain activity was 0·85 arbitrary units (a.u.; SD 0·70; n=39; a scaled magnitude of 1 a.u. represents the expected mean response to a heel lance in term-aged neonates) in the intervention group and 0·91 a.u. (SD 0·76; n=43) in the control group. Therefore, the primary outcome did not differ significantly between groups, with a mean difference of -0·11 a.u. (lower in intervention group; SD 0·77; 95% CI -0·42 to 0·20; p=0·38; n=82). No significant difference was observed across secondary outcomes. The PIPP-R difference in means was 1·10 (higher in intervention group, 95% CI -0·42 to 2·61; p=0·15; n=100); the odds ratio of becoming tachycardic was 2·08 (95% CI 0·46 to 9·46; p=0·34, n=105) in the intervention group with reference to the control group; and the difference in parental State-Trait Anxiety Inventory-State score was -0·44 (higher in control group; SD 6·85; 95% CI -2·91 to 2·02; p=0·72; n=106). One serious adverse event (desaturation) occurred in a neonate randomly assigned to the control group, which was not considered to be related to the study. INTERPRETATION: Parental stroking delivered at an optimal speed to activate C-tactile fibres for a duration of 10 s before the painful procedure did not significantly change neonates' magnitude of pain-related brain activity, PIPP-R score, or development of tachycardia. The trial highlighted the challenge of translating an experimental researcher-led tactile intervention into a parent-led approach, and the value of involving parents in their baby's pain management. FUNDING: Wellcome Trust and Bliss.Published version, accepted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
The characteristics and predictors of mortality in periprosthetic fractures around the knee
No full textAIMS: Periprosthetic fractures (PPFs) around the knee are challenging injuries. This study aims to describe the characteristics of knee PPFs and the impact of patient demographics, fracture types, and management modalities on in-hospital mortality. METHODS: Using a multicentre study design, independent of registry data, we included adult patients sustaining a PPF around a knee arthroplasty between 1 January 2010 and 31 December 2019. Univariate, then multivariable, logistic regression analyses were performed to study the impact of patient, fracture, and treatment on mortality. RESULTS: Out of a total of 1,667 patients in the PPF study database, 420 patients were included. The in-hospital mortality rate was 6.4%. Multivariable analyses suggested that American Society of Anesthesiologists (ASA) grade, history of peripheral vascular disease (PVD), history of rheumatic disease, fracture around a loose implant, and cerebrovascular accident (CVA) during hospital stay were each independently associated with mortality. Each point increase in ASA grade independently correlated with a four-fold greater mortality risk (odds ratio (OR) 4.1 (95% confidence interval (CI) 1.19 to 14.06); p = 0.026). Patients with PVD have a nine-fold increase in mortality risk (OR 9.1 (95% CI 1.25 to 66.47); p = 0.030) and patients with rheumatic disease have a 6.8-fold increase in mortality risk (OR 6.8 (95% CI 1.32 to 34.68); p = 0.022). Patients with a fracture around a loose implant (Unified Classification System (UCS) B2) have a 20-fold increase in mortality, compared to UCS A1 (OR 20.9 (95% CI 1.61 to 271.38); p = 0.020). Mode of management was not a significant predictor of mortality. Patients managed with revision arthroplasty had a significantly longer length of stay (median 16 days; p = 0.029) and higher rates of return to theatre, compared to patients treated nonoperatively or with fixation. CONCLUSION: The mortality rate in PPFs around the knee is similar to that for native distal femur and neck of femur fragility fractures. Patients with certain modifiable risk factors should be optimized. A national PPF database and standardized management guidelines are currently required to understand these complex injuries and to improve patient outcomes.0Not hel