St George's, University of London
  • London, England, United Kingdom
Recent publications
Background Pericardial defects are rare anatomical variations that can present as an isolated variation or be associated with other conditions. They are usually asymptomatic and misdiagnosed conditions, and given their rarity, partial pericardial defects can have devastating outcomes. The sudden death of an apparently healthy newborn certainly raises concerns, and a medico-legal investigation is crucial in establishing the cause of death. This case report highlights the importance of awareness on the part of obstetric professionals of the lethal outcomes of pericardial partial congenital defects. This case also demonstrates the difficulty of establishing a correct diagnosis. Case presentation The autopsy of a 15-h-old neonate revealed a partial pericardial defect ending in a biventricular strangulation by the defective pericardium. Other findings, such as the patency of the arterial ductus, a subarachnoid hemorrhage, and aspiration of amniotic fluid, were also reported. Conclusions Although imaging techniques have evolved, fetal detection of cardiac abnormalities can be tricky, especially when occurring as an isolated variation.
Background Congenital anomalies are the leading cause of perinatal, neonatal and infant mortality in developed countries. Large long-term follow-up studies investigating survival beyond the first year of life in children with rare congenital anomalies are costly and sufficiently large standardized cohorts are difficult to obtain due to the rarity of some anomalies. This study aimed to investigate the survival up to 10 years of age of children born with a rare structural congenital anomaly in the period 1995–2014 in Western Europe. Methods Live births from thirteen EUROCAT (European network for the epidemiological surveillance of congenital anomalies) population-based registries were linked to mortality records. Survival for 12,685 live births with one of the 31 investigated rare structural congenital anomalies (CAs) was estimated at 1 week, 4 weeks and 1, 5 and 10 years of age within each registry and combined across Europe using random effects meta-analyses. Differences between registries were evaluated for the eight rare CAs with at least 500 live births. Results Amongst the investigated CAs, arhinencephaly/holoprosencephaly had the lowest survival at all ages (58.1%, 95% Confidence Interval (CI): 44.3–76.2% at 1 week; 47.4%, CI: 36.4–61.6% at 1 year; 35.6%, CI: 22.2–56.9% at 10 years). Overall, children with rare CAs of the digestive system had the highest survival (> 95% at 1 week, > 84% at 10 years). Most deaths occurred within the first four weeks of life, resulting in a 10-year survival conditional on surviving 4 weeks of over 95% for 17 out of 31 rare CAs. A moderate variability in survival between participating registries was observed for the eight selected rare CAs. Conclusions Pooling standardised data across 13 European CA registries and the linkage to mortality data enabled reliable survival estimates to be obtained at five ages up to ten years. Such estimates are useful for clinical practice and parental counselling.
The National Osteoporosis Guideline Group (NOGG) has revised the UK guideline for the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women, and men age 50 years and older. Accredited by NICE, this guideline is relevant for all healthcare professionals involved in osteoporosis management. Introduction The UK National Osteoporosis Guideline Group (NOGG) first produced a guideline on the prevention and treatment of osteoporosis in 2008, with updates in 2013 and 2017. This paper presents a major update of the guideline, the scope of which is to review the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women, and men age 50 years and older. Methods Where available, systematic reviews, meta-analyses and randomised controlled trials were used to provide the evidence base. Conclusions and recommendations were systematically graded according to the strength of the available evidence. Results Review of the evidence and recommendations are provided for the diagnosis of osteoporosis, fracture-risk assessment and intervention thresholds, management of vertebral fractures, non-pharmacological and pharmacological treatments, including duration and monitoring of anti-resorptive therapy, glucocorticoid-induced osteoporosis, and models of care for fracture prevention. Recommendations are made for training; service leads and commissioners of healthcare; and for review criteria for audit and quality improvement. Conclusion The guideline, which has received accreditation from the National Institute of Health and Care Excellence (NICE), provides a comprehensive overview of the assessment and management of osteoporosis for all healthcare professionals involved in its management. This position paper has been endorsed by the International Osteoporosis Foundation and by the European Society for the Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases.
Background This case report highlights the importance of recognizing that ventricular ectopy may be a cause for syncope and sudden cardiac death, through triggered disorganized arrhythmia. In the context of syncope, ventricular ectopy should be carefully assessed for coupling interval and morphology. Case presentation A 39-year-old woman, who had presented with recurrent syncope, had a cardiac arrest shortly after admission that required emergency defibrillation. Review of her cardiac monitoring revealed an episode of polymorphic ventricular tachycardia which had degenerated into ventricular fibrillation. The dysrhythmia had been initiated by a short-coupled (R-on-T) ventricular ectopic (VE) beat. Anti-arrhythmic therapy was initiated in the form of hydroquinidine, but the patient continued to have frequent VEs of right bundle branch block (RBBB) morphology with a relatively narrow QRS complex and a variation in frontal axis. A cardiac MRI revealed late gadolinium enhancement of the posterior papillary muscle (indicative of focal scarring). The patient underwent electrophysiological mapping and catheter ablation of her ectopy. The patient made a good recovery and was discharged from hospital with a secondary prevention implantable cardioverter-defibrillator (ICD) in situ. Conclusions Short-couped VEs that are superimposed onto the preceding T wave (R-on-T) are indicative of electrical instability of the heart and should prompt urgent investigation. By studying the morphologies and axes of the QRS complexes produced by VEs, we can identify their likely origins and ascertain their clinical significance.
We read with interest the publication on malaria treatment by Obonyo et al. (Malaria J 21:30, 2022). This commentary questions the methodology, especially the chosen time points of treatment outcome measures.
Background Noninvasive ventilation (NIV) is a promising alternative to invasive mechanical ventilation (IMV) with a particular importance amidst the shortage of intensive care unit (ICU) beds during the COVID-19 pandemic. We aimed to evaluate the use of NIV in Europe and factors associated with outcomes of patients treated with NIV. Methods This is a substudy of COVIP study—an international prospective observational study enrolling patients aged ≥ 70 years with confirmed COVID-19 treated in ICU. We enrolled patients in 156 ICUs across 15 European countries between March 2020 and April 2021.The primary endpoint was 30-day mortality. Results Cohort included 3074 patients, most of whom were male (2197/3074, 71.4%) at the mean age of 75.7 years (SD 4.6). NIV frequency was 25.7% and varied from 1.1 to 62.0% between participating countries. Primary NIV failure, defined as need for endotracheal intubation or death within 30 days since ICU admission, occurred in 470/629 (74.7%) of patients. Factors associated with increased NIV failure risk were higher Sequential Organ Failure Assessment (SOFA) score (OR 3.73, 95% CI 2.36–5.90) and Clinical Frailty Scale (CFS) on admission (OR 1.46, 95% CI 1.06–2.00). Patients initially treated with NIV (n = 630) lived for 1.36 fewer days (95% CI − 2.27 to − 0.46 days) compared to primary IMV group (n = 1876). Conclusions Frequency of NIV use varies across European countries. Higher severity of illness and more severe frailty were associated with a risk of NIV failure among critically ill older adults with COVID-19. Primary IMV was associated with better outcomes than primary NIV. Clinical Trial Registration NCT04321265 , registered 19 March 2020, https://clinicaltrials.gov .
Background Abbreviated breast MRI (abMRI) is being introduced in breast screening trials and clinical practice, particularly for women with dense breasts. Upscaling abMRI provision requires the workforce of mammogram readers to learn to effectively interpret abMRI. The purpose of this study was to examine the diagnostic accuracy of mammogram readers to interpret abMRI after a single day of standardised small-group training and to compare diagnostic performance of mammogram readers experienced in full-protocol breast MRI (fpMRI) interpretation (Group 1) with that of those without fpMRI interpretation experience (Group 2). Methods Mammogram readers were recruited from six NHS Breast Screening Programme sites. Small-group hands-on workstation training was provided, with subsequent prospective, independent, blinded interpretation of an enriched dataset with known outcome. A simplified form of abMRI (first post-contrast subtracted images (FAST MRI), displayed as maximum-intensity projection (MIP) and subtracted slice stack) was used. Per-breast and per-lesion diagnostic accuracy analysis was undertaken, with comparison across groups, and double-reading simulation of a consecutive screening subset. Results 37 readers (Group 1: 17, Group 2: 20) completed the reading task of 125 scans (250 breasts) (total = 9250 reads). Overall sensitivity was 86% (95% confidence interval (CI) 84–87%; 1776/2072) and specificity 86% (95%CI 85–86%; 6140/7178). Group 1 showed significantly higher sensitivity (843/952; 89%; 95%CI 86–91%) and higher specificity (2957/3298; 90%; 95%CI 89–91%) than Group 2 (sensitivity = 83%; 95%CI 81–85% (933/1120) p < 0.0001; specificity = 82%; 95%CI 81–83% (3183/3880) p < 0.0001). Inter-reader agreement was higher for Group 1 (kappa = 0.73; 95%CI 0.68–0.79) than for Group 2 (kappa = 0.51; 95%CI 0.45–0.56). Specificity improved for Group 2, from the first 55 cases (81%) to the remaining 70 (83%) ( p = 0.02) but not for Group 1 (90–89% p = 0.44), whereas sensitivity remained consistent for both Group 1 (88–89%) and Group 2 (83–84%). Conclusions Single-day abMRI interpretation training for mammogram readers achieved an overall diagnostic performance within benchmarks published for fpMRI but was insufficient for diagnostic accuracy of mammogram readers new to breast MRI to match that of experienced fpMRI readers. Novice MRI reader performance improved during the reading task, suggesting that additional training could further narrow this performance gap.
Background: Extralevator abdominoperineal excisions (ELAPE) are now the accepted treatment option for low rectal cancers, which result in large perineal defects necessitating reconstruction. The aim of our study was to assess the clinical outcomes as well as the quality-of-life parameters (QOLP) following these reconstructions. Methods: A series of 27 patients who underwent ELAPE and immediate reconstruction with inferior gluteal artery perforator flaps (IGAP) between December 2013 to December 2018 were retrospectively analysed on patient demographics, disease and treatment, complications, and QOLP. Results: With a mean age of 71.6 years, all patients had low rectal cancers and underwent ELAPE (24 open, 3 lap-assisted) and immediate IGAP flap reconstruction. The follow-up period was 1 year. The overall perineal early minor complication rate was 25.9% and the early major complication rate of 14.8%. QOLP, such as tolerance to sit, perineal pain, perineal aesthetics, showed high patient satisfaction of 77.7%, 40.74%, and 66.6%, respectively at 1 year. The perineal hernia rate was 14.8% with all patients being female (p 0.0407; significant). Conclusion: IGAP flaps are a reliable option for reconstructing post-ELAPE defects with good patient satisfaction and outcomes.
Background Direct oral anticoagulants (DOACs) are effective and safe alternatives to warfarin for stroke prophylaxis for atrial fibrillation (AF). Whether this extends to patients at the extremes of body mass index (BMI) is unclear. Methods Using linked primary and secondary data, Jan 1, 2010 to Nov 30, 2018, we included CHA2DS2-VASC score ≥3 in women and ≥2 in men with AF treated with oral anticoagulants (OACs). Outcomes were ischaemic stroke, major bleeding and all-cause mortality by World Health Organisation BMI classification. Patients who received warfarin were propensity score matched (1:1 ratio) with those who received DOACs and the association of time-varying OAC exposure on outcomes quantified using Cox proportional hazards models. Findings We included 29,135 (22,818 warfarin, 6317 DOAC); 585 (2.0%) underweight, 8427 (28.9%) normal weight, 10,705 (36.7%) overweight, 5910 (20.3%) class I obesity and 3508 (12.0%) class II/III obesity. Patients treated with DOACs were older and more comorbid. After 3.7 (SD 2.5) years follow up, there was no difference in risk of ischaemic stroke and major bleeding by BMI category between DOACs and warfarin. Normal weight, overweight and obese class I patients had higher risk of all-cause mortality when treated with DOACs compared with warfarin (HR: 1.45 [95% CI 1.24–1.69], p < 0.001; 1.41 [95% CI 1.19–1.66], p < 0.001; and 1.90 [95% CI 1.50–2.39], p < 0.001), an effect not observed after DOACs became the most common OAC prescription. Amongst underweight patients OAC exposure was associated with greater harm from bleeding than benefit from stroke prevention (benefit to harm ratio, 0.35 [95% CI 0.26–0.44]). Interpretation In patients with AF in each BMI classification we found no difference in ischaemic stroke and bleeding risk for DOACs compared with warfarin. Underweight patients experienced divergent risk-benefit patterns from oral anticoagulation compared with other BMI categories. Funding None.
COVID‐19 causes significant thrombosis and coagulopathy, with elevated D‐dimer a predictor of adverse outcome. The precise mechanism of this coagulopathy remains unclear, one hypothesis is that loss of Angiotensin Converting Enzyme 2 activity during viral endocytosis leads to pro‐inflammatory angiotensin II accumulation, loss of angiotensin‐1‐7 and subsequent vascular endothelial activation. We undertook a double blind randomised, placebo controlled experimental medicine study to assess the effect of TRV027, a synthetic angiotensin‐1‐7 analogue on D‐dimer in 30 patients admitted to hospital with COVID‐19 (REC ref. 20/HRA/3414), Clinical Trial No. NCT04419610. The study showed a similar rate of adverse events in TRV027 and control groups. There was a numerical decrease in D‐dimer in the TRV027 group and increase in D‐dimer in the placebo group, however, this did not reach statistical significance (p=0.15). A Bayesian analysis demonstrated there was a 92% probability that this change represented a true drug effect.
Lysine-specific demethylase 5C (KDM5C) has been identified as an important chromatin remodeling gene, contributing to X-linked neurodevelopmental disorders (NDDs). The KDM5C gene, located in the Xp22 chromosomal region, encodes the H3K4me3-me2 eraser involved in neuronal plasticity and dendritic growth. Here we report 30 individuals carrying 13 novel and one previously identified KDM5C variants. Our cohort includes the first reported case of somatic mosaicism in a male carrying a KDM5C nucleotide substitution, and a dual molecular finding in a female carrying a homozygous truncating FUCA1 alteration together with a de novo KDM5C variant. With the use of next generation sequencing strategies, we detected 1 frameshift, 1 stop codon, 2 splice-site and 10 missense variants, which pathogenic role was carefully investigated by a thorough bioinformatic analysis. The pattern of X-chromosome inactivation was found to have an impact on KDM5C phenotypic expression in females of our cohort. The affected individuals of our case series manifested a neurodevelopmental condition characterized by psychomotor delay, intellectual disability with speech disorders, and behavioral features with particular disturbed sleep pattern; other observed clinical manifestations were short stature, obesity and hypertrichosis. Collectively, these findings expand the current knowledge about the pathogenic mechanisms leading to dysfunction of this important chromatin remodeling gene and contribute to a refinement of the KDM5C phenotypic spectrum.
While the endocrine function of white adipose tissue has been extensively explored, comparatively little is known about the secretory activity of less-investigated fat depots. Here, we use proteomics to compare the secretory profiles of male murine perivascular depots with those of canonical white and brown fat. Perivascular secretomes show enrichment for neuronal cell-adhesion molecules, reflecting a higher content of intra-parenchymal sympathetic projections compared to other adipose depots. The sympathetic innervation is reduced in the perivascular fat of obese ( ob/ob ) male mice, as well as in the epicardial fat of patients with obesity. Degeneration of sympathetic neurites is observed in presence of conditioned media of fat explants from ob/ob mice, that show reduced secretion of neuronal growth regulator 1. Supplementation of neuronal growth regulator 1 reverses this neurodegenerative effect, unveiling a neurotrophic role for this protein previously identified as a locus associated with human obesity. As sympathetic stimulation triggers energy-consuming processes in adipose tissue, an impaired adipose-neuronal crosstalk is likely to contribute to the disrupted metabolic homeostasis characterising obesity.
In 2020, 21% of people who sought asylum in the UK were children. This population has complex interconnecting health and social needs. Assessment requires a holistic approach, with consideration of physical and mental health in addition to social and developmental well-being, within the whole family group. A trauma-informed life-cycle and intergenerational care approach is important. This article, aimed at all health professionals who may work with asylum-seeking families, outlines the best practice principles for undertaking health assessments in migrant children and young people.
Background: Single, high-dose liposomal amphotericin B (LAmB; AmBisome, Gilead Sciences) has demonstrated non-inferiority to amphotericin B deoxycholate in combination with other antifungals for averting all-cause mortality from HIV-associated cryptococcal meningitis. There are limited data on the pharmacokinetics (PK) of AmBisome. The aim of this study was to describe population PK of AmBisome and conduct a meta-analysis of the available studies to suggest the optimal dosing for cryptococcal meningoencephalitis. Methods: Data from a Phase II and Phase III trial of high-dose, short-course AmBisome for cryptococcal meningoencephalitis were combined to develop a population PK model. A search was conducted for trials of AmBisome monotherapy and meta-analysis of clinical outcome data was performed. Results: A two-compartment model with first-order clearance of drug from the central compartment fitted the data best and enabled the extent of inter-individual variability in PK to be quantified. Mean (SD) population PK parameter estimates were: clearance 0.416 (0.363) L/h; volume of distribution 4.566 (4.518) L; first-order transfer of drug from central to peripheral compartments 2.222 (3.351) h-1, and from peripheral to central compartment 2.951 (4.070) h-1. Data for the meta-analysis were insufficient to suggest optimal dosing of AmBisome for cryptococcal meningoencephalitis. Conclusions: This study provides novel insight into the PK of AmBisome at the population level and the variability therein. Our analysis also serves to highlight the paucity of data available on the pharmacodynamics (PD) of AmBisome and underscores the importance of thorough and detailed PK/PD analysis in the development of novel antifungals, by demonstrating the challenges associated with post hoc PK/PD analysis.
The aim of any surgical training programme is to produce competent, effective, and safe individuals, who will go on to deliver high quality patient care, for a prolonged period at an affordable cost. The fundamental principles of surgical training have remained unchanged for years, despite there being increasing concerns relating to trainee recruitment, retention, and morale. There is no benefit in ascribing shortcomings of surgical training to uncontrollable factors such as the European Working Time Directive, unprecedented NHS service demand following COVID-19 and economic uncertainty. Instead, we must look introspectively at existing opportunities for improvement in order to continue to produce high quality surgeons in the NHS.
Purpose Monocyte distribution width (MDW) is a biomarker for the early identification of sepsis. We assessed its accuracy in patients presenting with suspected sepsis in the emergency department (ED). Methods This was a single gate, single centre study in consecutive adults (≥ 18 years) admitted to the ED with suspected sepsis and clinical history compatible with infection, between 01 January and 31 December 2020 ( n = 2570). Results The overall median MDW was 22.0 (IQR 19.3, 25.6). Using Sepsis-3 (qSOFA) to define sepsis, the Area Under Curve (AUC) for a receiver operator characteristic (ROC) relationship was 0.59 (95% CI 0.56, 0.61). Discrimination was similar using other clinical scores, and to that of C-reactive protein. At an MDW cutoff of 20.0, sensitivity was 0.76 (95% CI 0.73, 0.80) and specificity 0.35 (95% CI 0.33, 0.37) for Sepsis-3. MDW showed better performance to discriminate infection, with AUC 0.72 (95% CI 0.69, 0.75). At MDW 20.0, sensitivity for infection was 0.72 (95% CI 0.70, 0.74) and specificity 0.64 (95% CI 0.59, 0.70). A sensitivity analysis excluding coronavirus disease (COVID-19) admissions ( n = 552) had no impact on the AUC. MDW distribution at admission was similar for bacteraemia and COVID-19. Conclusions In this population of ED admissions with a strong clinical suspicion of sepsis, MDW had a performance to identify sepsis comparable to that of other commonly used biomarkers. In this setting, MDW could be a useful additional marker of infection.
Primary progressive aphasia (PPA) is a group of neurodegenerative disorders featuring primary-language impairments and typically classified into three-variants: semantic, non-fluent and logopenic. Yet their language profiles significantly overlap. Language deficits can also occur in other frontotemporal dementias (FTD) like progressive supranuclear palsy and corticobasal syndrome, suggesting that language symptoms are transdiagnostic. Though brain atrophy determines language difficulties, similar atrophy profiles often are related to different language deficits, and different atrophies can cause similar impairments (e.g., logopenic/non-fluent PPA). We apply a transdiagnotic approach to link the language variantions across FTD-PPA spectrum to their underlying neuroanatomical factors. Principal component analysis identified three language dimensions (motor-speech/phonology, semantics and syntax) and thirteen atrophic dimensions, including temporal, frontal, parietal regions. While anterior temporal lobe atrophy predicts semantic impairments, frontoparietal atrophies predict motor-speech/phonology, and syntax. Atrophy and language variations across FTD-PPA syndromes are deconstructed on a brain-behaviour continuum, with only semantic variants being clearly separate.
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3,875 members
Sebastian Fuller
  • Center for Infection and Immunity Research
Kristiana Gordon
  • Cardiovascular Sciences Research Centre
Rachel L Allen
  • Medical School
Florence Rosie Avila Hogg
  • Atkinson Morley Regional Neuroscience Centre
Catrin E Moore
  • Infection and Immunity
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