Charles Hinds | Queen Mary, University of London (original) (raw)

Papers by Charles Hinds

Nature

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we h... more Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49...

<b>Copyright information:</b>Taken from "Identification and characterisation of ... more <b>Copyright information:</b>Taken from "Identification and characterisation of the high-risk surgical population in the United Kingdom"Critical Care 2006;10(3):R81-R81.Published online 2 Jun 2006PMCID:PMC1550954.h an overall mortality rate of less than 5%; high risk, subpopulation of patients undergoing a procedure with an overall mortality rate of 5% or more. ICNARC database: ICU, general surgical patients admitted directly to the intensive care unit following surgery; ward to ICU, patients admitted to the intensive care unit following initial postoperative care on a standard ward.

Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune s... more Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care1or hospitalisation2;3;4following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study recruits critically-ill cases and compares their genomes with population controls in order to find underlying disease mechanisms.Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisat...

Journal of the Intensive Care Society, 2003

This years Council meeting was held in the ESICM Offices out near the Airport which is an interes... more This years Council meeting was held in the ESICM Offices out near the Airport which is an interesting drive from Gare Midi across the part of Brussels not advertised in the travel brochures. It is curious to note that the high speed link between Waterloo and the Brussels Office is still incomplete between London and the Tunnel but also between Central Brussels and the Offices. Hence the cab. However the weather was great with the sun shining over the rather modern Industrial Estate and with the cerulean blue skies reflected in the windows of the Erasme Hospital.

We present a case of coronary artery bypass grafting in a 78-year-old man with triple vessel dise... more We present a case of coronary artery bypass grafting in a 78-year-old man with triple vessel disease and concomitant cardiac amyloidosis. Postoperatively he developed a profound low cardiac output state and multi-organ failure. He died 3 weeks following surgery. Bypass surgery is rarely performed in patients with cardiac amyloidosis, and there is little in the literature regarding outcomes. The few published cases present a bleak picture, and hence percutaneous coronary intervention should always be preferred.

EBioMedicine, 2016

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection.... more Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. For its clinical course, host genetic factors are important and rare genomic variants are suspected to contribute. We sequenced the exomes of 59 Greek and 15 German patients with bacterial sepsis divided into two groups with extremely different disease courses. Variant analysis was focusing on rare deleterious single nucleotide variants (SNVs). We identified significant differences in the number of rare deleterious SNVs per patient between the ethnic groups. Classification experiments based on the data of the Greek patients allowed discrimination between the disease courses with estimated sensitivity and specificity N 75%. By application of the trained model to the German patients we observed comparable discriminatory properties despite lower population-specific rare SNV load. Furthermore, rare SNVs in genes of cell signaling and innate immunity related pathways were identified as classifiers discriminating between the sepsis courses. Sepsis patients with favorable disease course after sepsis, even in the case of unfavorable preconditions, seem to be affected more often by rare deleterious SNVs in cell signaling and innate immunity related pathways, suggesting a protective role of impairments in these processes against a poor disease course.

Critical Care, 2006

Measurements of central venous oxygen saturation (ScvO 2) have been successfully used to guide ha... more Measurements of central venous oxygen saturation (ScvO 2) have been successfully used to guide haemodynamic therapy in critical care. The efficacy of this approach in the treatment of severe sepsis and septic shock has stimulated interest in the use of ScvO 2 to guide management in patients undergoing major surgery. The physiological basis of ScvO 2 measurement is complex. A number of outstanding issues will need to be resolved before incorporating ScvO 2 measurement into routine practice. First, it is not yet clear which value of ScvO 2 should be targeted. Second, there is some uncertainty as to which interventions are the most effective for achieving the desired value of ScvO 2 or how long this value should be maintained. The study by The Collaborative Study Group on Perioperative ScvO 2 Monitoring published in this edition of Critical Care may help provide answers to some of these questions. Our understanding of ScvO 2 measurement remains limited, however, and the routine use of peri-operative ScvO 2guided goal-directed therapy cannot be recommended until a large randomised trial has confirmed the value of this approach.

The Lancet, 1993

Scoring systems designed to rate the severity of an illness are being used for comparison of hosp... more Scoring systems designed to rate the severity of an illness are being used for comparison of hospital units to identify different standards of care and to allocate resources. One such scoring system is the Acute Physiology and Chronic Health Evaluation (APACHE) system which is designed to assess the severity of illness of patients in intensive care units (ICUs). It is widely assumed that different ICUs can be compared by the ratio of actual mortality to that predicted by the APACHE score. However, we suggest that the use of physiological data that can be influenced by medical and nursing intervention should not be used for audit. For example, by good care a patient may be made less severely ill and, therefore, may have a lower actual mortality while, at the same time, accumulating only a low APACHE score with low predicted mortality. This patient could have, therefore, the same mortality ratio as a patient treated inappropriately, who may have a higher actual mortality and a high APACHE score with greater predicted mortality. Paradoxically, the very accuracy of these scoring systems for assessing the severity of illness precludes their use for comparison and audit.

Journal of Psychosomatic Research, 1994

Post-operative fatigue is an important subjective problem for surgical patients, but its basis is... more Post-operative fatigue is an important subjective problem for surgical patients, but its basis is unknown, and the possibility of a psychological component has been neglected. To investigate its putative physiological and psychological bases, 74 patients undergoing coronary artery bypass graft surgery were studied. Circulating catecholamine levels were measured at intervals perioperatively and questionnaires were used to measure fatigue, depression and anxiety up to 30 days post-operatively. We tested whether fatigue was related either to the catecholamine or to the emotional responses to surgery. The second element to the design was a controlled randomized study: patients underwent different forms of psychological preparation or a no-treatment control procedure in an attempt to test whether post-operative fatigue was amenable to psychological manipulation. Psychological preparation had no effect. Fatigue at 30 days was greatest in patients whose noradrenaline levels were greatest perioperatively. Independently of this relationship, fatigue at 30 days correlated with concurrent levels of depression and anxiety. Post-operative fatigue has both physiological and psychological correlates.

The Journal of Clinical Endocrinology & Metabolism, 1998

We report the emergency and prolonged use of etomidate to control circulating cortisol levels in ... more We report the emergency and prolonged use of etomidate to control circulating cortisol levels in a patient with Cushing's syndrome secondary to ectopic ACTH production from a pancreatic islet cell tumor. Duodenal perforation and peritonitis complicated an episode of salmonella septicemia, precluding the use of conventional oral medical adrenolytic therapy. Endogenous cortisol secretion was abolished by parenteral etomidate, allowing serum cortisol levels to be controlled with an iv infusion of hydrocortisone over an 8-week period in intensive care before definitive pancreatic surgery.

Intensive Care Medicine, 1984

We have developed a technique for simulating artificially ventilated patients using a computer mo... more We have developed a technique for simulating artificially ventilated patients using a computer model of the respiratory system and have investigated its ability to predict the patient's response to alterations in the ventilation regime. The majority of those studied were in a stable condition following cardiac surgery. Predictions for PaO 2 showed a reasonable correlation with measured values (r = 0.94), although individual predictions could differ appreciably (SEE = + 17.3 mmHg). Predictions for PaCO 2 correlated less well (i" = 0.89, SEE = _+ 2.0 mmHg) and there was a consistent tendency to overestimate this variable. The least accurate predictions were those for P~O 2 (r = 0.61, SEE = _+ 3.8 mmHg). Errors in prediction were attributable to deficiencies in the model (most importantly the three-compartment lung and the modelling of CO 2 production, storage and excretion), compounded by unpredictable alterations in the patient's physiology (mainly Vo2, £/CO2 and 0t)-However, allowing for accepted clinical variability and routine measurement accuracy, the predictions are generally reasonable. This suggests that, with some further modifications, computer modelling of this, and other, systems may prove to be a clinically and educationally useful technique.

Intensive Care Medicine, 1982

There are considerable logistical difficulties involved in providing an adequate training program... more There are considerable logistical difficulties involved in providing an adequate training programme for each new doctor when starting intensive care. One solution is to use an interactive computer terminal and provide programmes for self-instruction and assessment. Using a computer model of the respiratory system linked to a computer-assisted instructional driver we have developed instructional exercises on the management of artificial ventilation and the treatment of respiratory failure. Each teaching session contains explanatory text, multiple choice questions and model simulations. The student can interact with the simulations, appropriate assistance being provided when required, while his answers are marked and assessed with further explanation when necessary. The use of computer models adds a new dimension to computer-assisted learning techniques and is particularly applicable to intensive care medicine.

Infection and Immunity, 2005

Previous studies have indicated that peptidoglycan (PepG) from gram-positive bacteria can exert a... more Previous studies have indicated that peptidoglycan (PepG) from gram-positive bacteria can exert a priming effect on the innate immune response to lipopolysaccharide (LPS) from gram-negative bacteria. Here, we hypothesized that this priming effect may be preceded by enhanced expression of monocyte CD14, Toll-like receptor 2 (TLR2), and TLR4. In an ex vivo whole human blood model, we observed a substantial synergy between LPS and PepG in the release of tumor necrosis factor alpha and interleukin-1β (IL-1β) over the 24-h experimental period, whereas the effect on IL-8 and IL-10 release was more time dependent. The priming effect of PepG on cytokine release was preceded by a rapid upregulation of CD14, TLR2, and TLR4 expression on monocytes: at 3 hours there was a twofold increase in CD14 expression ( P < 0.03), a fivefold increase in TLR2 expression ( P < 0.03), and a twofold increase in TLR4 expression ( P < 0.03). CD14 and TLR2 remained upregulated throughout the experimenta...

Current Opinion in Anaesthesiology, 2000

Neuromuscular weakness is a very common and debilitating problem for survivors of critical illnes... more Neuromuscular weakness is a very common and debilitating problem for survivors of critical illness. Neurophysiological abnormalities are almost ubiquitous in these patients, and often favour a diagnosis of axonal polyneuropathy, whereas muscle histology, where available, reveals a high incidence of atrophy and necrosis. The precise nature and aetiology of this complex disorder is not yet well understood. Curr Opin Anaesthesiol 13:93±98.

Critical Care Medicine, 2004

Critical Care, 2013

Introduction: The effects of dopexamine, a β2-agonist, on perioperative and sepsis-related hemody... more Introduction: The effects of dopexamine, a β2-agonist, on perioperative and sepsis-related hemodynamic, microvascular, immune, and organ dysfunction are controversial and poorly understood. We investigated these effects in a rodent model of laparotomy and endotoxemia. Methods: In two experiments, 80 male Wistar rats underwent laparotomy. In 64 rats, this was followed by administration of endotoxin; the remainder (16) underwent sham endotoxemia. Endotoxemic animals received either dopexamine at 0.5, 1, or 2 μg/kg/min or 0.9% saline vehicle (controls) as resuscitation fluid. The effects of dopexamine on global hemodynamics, mesenteric regional microvascular flow, renal and hepatic function and immune activation were evaluated. Results: Endotoxin administration was associated with a systemic inflammatory response (increased plasma levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10, as well as cell-adhesion molecules CD11a and CD11b), and increased pulmonary myeloperoxidase (MPO) activity (indicating pulmonary leukocyte infiltration), whereas biochemical changes demonstrated lactic acidosis with significant renal and hepatic injury. Dopexamine administration was associated with less-severe lactic acidosis (pooled dopexamine versus controls, (lactate, 2.2 mM ± 0.2 mM versus 4.0 mM ± 0.5 mM; P < 0.001) and reductions in the systemic inflammatory response (pooled dopexamine versus control, 4 hour (TNF-α): 324 pg/ml ± 93 pg/ml versus 97 pg/ml ± 14 pg/ml, p < 0.01), pulmonary myeloperoxidase (MPO) activity, and hepatic and renal injury (pooled dopexamine versus control (ALT): 81 IU/L ± 4 IU/L versus 138 IU/L ± 25 IU/L; P < 0.05; (creatinine): 49.4 μM ± 3.9 μM versus 76.2 μM ± 9.8 μM; P < 0.005). However, in this study, clinically relevant doses of dopexamine were not associated with clinically significant changes in MAP, CI, or gut regional microvascular flow.

Critical Care, 2010

Introduction: Post-operative outcomes may be improved by the use of flow related end-points for i... more Introduction: Post-operative outcomes may be improved by the use of flow related end-points for intravenous fluid and/or low dose inotropic therapy. The mechanisms underlying this benefit remain uncertain. The objective of this study was to assess the effects of stroke volume guided intravenous fluid and low dose dopexamine on tissue microvascular flow and oxygenation and inflammatory markers in patients undergoing major gastrointestinal surgery. Methods: Randomised, controlled, single blind study of patients admitted to a university hospital critical care unit following major gastrointestinal surgery. For eight hours after surgery, intravenous fluid therapy was guided by measurements of central venous pressure (CVP group), or stroke volume (SV group). In a third group stroke volume guided fluid therapy was combined with dopexamine (0.5 mcg/kg/min) (SV & DPX group). Results: 135 patients were recruited (n = 45 per group). In the SV & DPX group, increased global oxygen delivery was associated with improved sublingual (P < 0.05) and cutaneous microvascular flow (P < 0.005) (sublingual microscopy and laser Doppler flowmetry). Microvascular flow remained constant in the SV group but deteriorated in the CVP group (P < 0.05). Cutaneous tissue oxygen partial pressure (PtO 2) (Clark electrode) improved only in the SV & DPX group (P < 0.001). There were no differences in serum inflammatory markers. There were no differences in overall complication rates between the groups although acute kidney injury was more frequent in the CVP group (CVP group ten patients (22%); pooled SV and SV & DPX groups seven patients (8%); P = 0.03) (post hoc analysis). Conclusions: Stroke volume guided fluid and low dose inotropic therapy was associated with improved global oxygen delivery, microvascular flow and tissue oxygenation but no differences in the inflammatory response to surgery. These observations may explain improved clinical outcomes associated with this treatment in previous trials.