Queen Elizabeth Hospital

Background While it is now apparent clinical sequelae (long COVID) may persist after acute COVID-19, their nature, frequency and aetiology are poorly characterised. This study aims to regularly synthesise evidence on long COVID characteristics, to help inform clinical management, rehabilitation strategies and interventional studies to improve long-term outcomes. Methods A living systematic review. Medline, CINAHL (EBSCO), Global Health (Ovid), WHO Global Research on COVID-19 database, LitCovid and Google Scholar were searched till 17 March 2021. Studies including at least 100 people with confirmed or clinically suspected COVID-19 at 12 weeks or more post onset were included. Risk of bias was assessed using the tool produced by Hoy et al . Results were analysed using descriptive statistics and meta-analyses to estimate prevalence. Results A total of 39 studies were included: 32 cohort, 6 cross-sectional and 1 case–control. Most showed high or moderate risk of bias. None were set in low-income countries and few included children. Studies reported on 10 951 people (48% female) in 12 countries. Most included previously hospitalised people (78%, 8520/10 951). The longest mean follow-up time was 221.7 (SD: 10.9) days post COVID-19 onset. Over 60 physical and psychological signs and symptoms with wide prevalence were reported, most commonly weakness (41%; 95% CI 25% to 59%), general malaise (33%; 95% CI 15% to 57%), fatigue (31%; 95% CI 24% to 39%), concentration impairment (26%; 95% CI 21% to 32%) and breathlessness (25%; 95% CI 18% to 34%). 37% (95% CI 18% to 60%) of patients reported reduced quality of life; 26% (10/39) of studies presented evidence of reduced pulmonary function. Conclusion Long COVID is a complex condition with prolonged heterogeneous symptoms. The nature of studies precludes a precise case definition or risk evaluation. There is an urgent need for prospective, robust, standardised, controlled studies into aetiology, risk factors and biomarkers to characterise long COVID in different at-risk populations and settings. PROSPERO registration number CRD42020211131.

The indications for transfusing fresh-frozen plasma (FFP), cryoprecipitate and cryosupernatant plasma are very limited. When transfused they can have unpredictable adverse effects. The risks of transmitting infection are similar to those of other blood components unless a pathogen-reduced plasma (PRP) is used. Of particular concern are allergic reactions and anaphylaxis, transfusion-related acute lung injury, and haemolysis from transfused antibodies to blood group antigens, especially A and B. FFP is not indicated in disseminated intravascular coagulation without bleeding, is only recommended as a plasma exchange medium for thrombotic thrombocytopenic purpura (for which cryosupernatant is a possible alternative), should never be used to reverse warfarin anticoagulation in the absence of severe bleeding, and has only a very limited place in prophylaxis prior to liver biopsy. When used for surgical or traumatic bleeding, FFP and cryoprecipitate doses should be guided by coagulation studies, which may include near-patient testing. FFP is not indicated to reverse vitamin K deficiency for neonates or patients in intensive care units. PRP may be used as an alternative to FFP. In the UK, PRP from countries with a low bovine spongiform encephalopathy incidence is recommended by the Departments of Health for children born after 1 January 1996. Arrangements for limited supplies of single donor PRP of non-UK origin are expected to be completed in 2004. Batched pooled commercially prepared PRP from donors in the USA (Octaplas) is licensed and available in the UK. FFP must be thawed using a technique that avoids risk of bacterial contamination. Plastic packs containing any of these plasma products are brittle in the frozen state and must be handled with care.

BACKGROUND: Whole brain radiotherapy (WBRT) and dexamethasone are widely used to treat brain metastases from non-small cell lung cancer (NSCLC), although there have been no randomised clinical trials showing that WBRT improves either quality of life or overall survival. Even after treatment with WBRT, the prognosis of this patient group is poor. We aimed to establish whether WBRT could be omitted without a significant effect on survival or quality of life. METHODS: The Quality of Life after Treatment for Brain Metastases (QUARTZ) study is a non-inferiority, phase 3 randomised trial done at 69 UK and three Australian centres. NSCLC patients with brain metastases unsuitable for surgical resection or stereotactic radiotherapy were randomly assigned (1:1) to optimal supportive care (OSC) including dexamethasone plus WBRT (20 Gy in five daily fractions) or OSC alone (including dexamethasone). The dose of dexamethasone was determined by the patients' symptoms and titrated downwards if symptoms improved. Allocation to treatment group was done by a phone call from the hospital to the Medical Research Council Clinical Trials Unit at University College London using a minimisation programme with a random element and stratification by centre, Karnofsky Performance Status (KPS), gender, status of brain metastases, and the status of primary lung cancer. The primary outcome measure was quality-adjusted life-years (QALYs). QALYs were generated from overall survival and patients' weekly completion of the EQ-5D questionnaire. Treatment with OSC alone was considered non-inferior if it was no more than 7 QALY days worse than treatment with WBRT plus OSC, which required 534 patients (80% power, 5% [one-sided] significance level). Analysis was done by intention to treat for all randomly assigned patients. The trial is registered with ISRCTN, number ISRCTN3826061. FINDINGS: Between March 2, 2007, and Aug 29, 2014, 538 patients were recruited from 69 UK and three Australian centres, and were randomly assigned to receive either OSC plus WBRT (269) or OSC alone (269). Baseline characteristics were balanced between groups, and the median age of participants was 66 years (range 38-85). Significantly more episodes of drowsiness, hair loss, nausea, and dry or itchy scalp were reported while patients were receiving WBRT, although there was no evidence of a difference in the rate of serious adverse events between the two groups. There was no evidence of a difference in overall survival (hazard ratio 1·06, 95% CI 0·90-1·26), overall quality of life, or dexamethasone use between the two groups. The difference between the mean QALYs was 4·7 days (46·4 QALY days for the OSC plus WBRT group vs 41·7 QALY days for the OSC group), with two-sided 90% CI of -12·7 to 3·3. INTERPRETATION: Although the primary outcome measure result includes the prespecified non-inferiority margin, the combination of the small difference in QALYs and the absence of a difference in survival and quality of life between the two groups suggests that WBRT provides little additional clinically significant benefit for this patient group. FUNDING: Cancer Research UK, Medical Research Council Clinical Trials Unit at University College London, and the National Health and Medical Research Council in Australia.

A large multicentre study on the short and long term clinical and developmental outcome of infants randomised to different diets is being undertaken. This report represents an interim analysis of the early postnatal growth performance of an unselected population of 194 preterm infants (gestation, mean (SD) 31 . 0 (2 . 9) weeks; birthweight, mean (SD) 1364 (294) g), both ill and well, examined in two (of four) parallel trials. One trial compared banked breast milk with a new preterm formula (primary trial); the other compared these diets as supplements to maternal milk (supplement trial). A major dietary effect on the number of days taken to regain birthweight and subsequent gains in weight, length, and head circumference was observed in the primary trial. Infants fed banked breast milk and weighing less than 1200 g at birth took a calculated additional three weeks to reach 2000 g compared with those fed on the preterm formula. A significant influence of diet on body proportions was seen in the relation between body weight, head circumference, and length. Similar though smaller differences in growth patterns were seen in the supplement trial. By the time they reach 2000 g, infants of birthweights 1200 to 1849 g fed on banked breast milk and infants below 1200 g fed on either banked breast milk or maternal milk supplemented (as necessary) with banked breast milk, fulfilled stringent criteria for failure to thrive (weight less than 2 SD below the mean for age). Only infants fed the preterm formula as their sole diet had maintained their birth centile by discharge from hospital. The misleading nature of comparisons between extrauterine and intrauterine steady state weight gains is emphasised.

These Joint British Diabetes Societies guidelines, commissioned by NHS Diabetes, for the perioperative management of the adult patient undergoing surgery are available in full in the Supporting Information. This document goes through the seven stages of the patient journey when having surgery. These are: primary care referral; surgical outpatients; preoperative assessment; hospital admission; surgery; post-operative care; discharge. Each stage is given its own considerations, outlining the roles and responsibilities of each group of healthcare professionals. The evidence base for the recommendations made at each stage, discussion of controversial areas and references are provided in the report. This document has two key recommendations. Firstly, that the management of the elective adult surgery patients should be with modification to their usual diabetes treatment if the fasting is minimized because the routine use of a variable rate intravenous insulin infusion is not recommended. Secondly, that poor preoperative glycaemic control leads to post-outcomes and thus, where appropriate, needs to be addressed prior to referral for surgery.

Metabolomic studies of body fluids show that immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) are associated with metabolic disruption. This is likely to reflect the increased bioenergetic and biosynthetic demands of sustained inflammation and changes in nutrient and oxygen availability in damaged tissue. The synovial membrane lining layer is the principal site of inflammation in RA. Here, the resident cells are fibroblast-like synoviocytes (FLS) and synovial tissue macrophages, which are transformed toward overproduction of enzymes that degrade cartilage and bone and cytokines that promote immune cell infiltration. Recent studies have shown metabolic changes in both FLS and macrophages from RA patients, and these may be therapeutically targetable. However, because the origins and subset-specific functions of synoviocytes are poorly understood, and the signaling modules that control metabolic deviation in RA synovial cells are yet to be explored, significant additional research is needed to translate these findings to clinical application. Furthermore, in many inflamed tissues, different cell types can forge metabolic collaborations through solute carriers in their membranes to meet a high demand for energy or biomolecules. Such relationships are likely to exist in the synovium and have not been studied. Finally, it is not yet known whether metabolic change is a consequence of disease or whether primary changes to cellular metabolism might underlie or contribute to the pathogenesis of early-stage disease. In this review article, we collate what is known about metabolism in synovial tissue cells and highlight future directions of research in this area.

This guideline updates and replaces the 5th edition of the Standards of Monitoring published in 2015. The aim of this document is to provide guidance on the minimum standards for monitoring of any patient undergoing anaesthesia or sedation under the care of an anaesthetist. The recommendations are primarily aimed at anaesthetists practising in the UK and Ireland, but it is recognised that these guidelines may also be of use in other areas of the world. Minimum standards for monitoring patients during anaesthesia and in the recovery phase are included. There is also guidance on monitoring patients undergoing sedation and during transfer. There are new sections specifically discussing capnography, sedation and regional anaesthesia. In addition, the indications for processed electroencephalogram and neuromuscular monitoring have been updated.

OBJECTIVE: Leakage of fluid from the subglottic space to the lungs occurs along the longitudinal folds within the wall of an inflated high-volume, low-pressure (HVLP) cuff. The low-volume, low-pressure (LVLP) cuff does not have these folds yet allows for convenient and reliable control of tracheal wall pressure. Pulmonary aspiration during anesthesia has been linked with postoperative pneumonia and during critical illness causes ventilator-associated pneumonia. DESIGN: Prospective, blinded, randomized controlled trial; prospective observational study; and benchtop models. SETTING: Department of Anaesthesia and Critical Care, Queen Elizabeth Hospital. PATIENTS: Anesthetized patients (n=38) and critically ill patients with either an LVLP or HVLP cuffed tracheostomy tube following swallow assessments (n=67). INTERVENTIONS: The LVLP cuff was compared with HVLP cuffs for leakage of dye placed in the subglottic space to the tracheobronchial tree in a rigid tracheal model and a benchtop pig trachea model (before and after a standardized cuff movement). MEASUREMENTS AND MAIN RESULTS: In the rigid tracheal model, the incidence of leakage was 0% in the LVLP group and 100% in the HVLP group (p<.01). Dye leakage in the pig tracheal model with HVLP cuffs was 44% before tube movement, increasing to 79% afterward. The LVLP cuff did not leak in the pig tracheal model. Dye leakage in anesthetized patients was 0% before movement and 5% after in the LVLP group and in the HVLP group 22% increasing to 67% after movement (p<.001). Forty-nine percent of swallow assessments were scored as failed in the critical care patients with HVLP tracheostomy tube cuffs, and there were no episodes of aspiration following swallow assessment in the LVLP group (p<.05). CONCLUSIONS: The LVLP cuffed tracheal and tracheostomy tubes reduced pulmonary aspiration in the benchtop models and in anesthetized and critically ill patients. The single failure of the LVLP cuff in the anesthesia group was probably associated with accidental endobronchial intubation following tube movement.

Studies on head injury-induced pituitary dysfunction are limited in number and conflicting results have been reported. To further clarify this issue, 29 consecutive patients (24 males), with severe (n = 21) or moderate (n = 8) head trauma, having a mean age of 37 17 years were investigated in the immediate post-trauma period. All patients required mechanical ventilatory support for 8-55 days and were enrolled in the study within a few days before ICU discharge. Basal hormonal assessment included measurement of cortisol, corticotropin, free thyroxine (fT4), thyrotropin (TSH), testosterone (T) in men, estradiol (E2) in women, prolactin (PRL), and growth hormone (GH). Cortisol and GH levels were measured also after stimulation with 100 g human corticotropin releasing hormone (hCRH) and 100 g growth hormone releasing hormone (GHRH), respectively. Cortisol hyporesponsiveness was considered when peak cortisol concentration was less than 20 g/dl following hCRH. TSH deficiency was diagnosed when a subnormal serum fT4 level was associated with a normal or low TSH. Hypogonadism was considered when T (males) or E2 (women) were below the local reference ranges, in the presence of normal PRL levels. Severe or partial GH deficiencies were defined as a peak GH below 3 g/l or between 3 and 5 g/l, respectively, after stimulation with GHRH. Twenty-one subnormal responses were found in 15 of the 29 patients (52%) tested; seven (24%) had hypogonadism, seven (24%) had cortisol hyporesponsiveness, five (17%) had hypothyroidism, and two patients (7%) had partial GH deficiency.

Snakebite remains a neglected medical problem of the developing world with up to 125,000 deaths each year despite more than a century of calls to improve snakebite prevention and care. An estimated 75% of fatalities from snakebite occur outside the hospital setting. Because phospholipase A2 (PLA2) activity is an important component of venom toxicity, we sought candidate PLA2 inhibitors by directly testing drugs. Surprisingly, varespladib and its orally bioavailable prodrug, methyl-varespladib showed high-level secretory PLA2 (sPLA2) inhibition at nanomolar and picomolar concentrations against 28 medically important snake venoms from six continents. In vivo proof-of-concept studies with varespladib had striking survival benefit against lethal doses of Micrurus fulvius and Vipera berus venom, and suppressed venom-induced sPLA2 activity in rats challenged with 100% lethal doses of M. fulvius venom. Rapid development and deployment of a broad-spectrum PLA2 inhibitor alone or in combination with other small molecule inhibitors of snake toxins (e.g., metalloproteases) could fill the critical therapeutic gap spanning pre-referral and hospital setting. Lower barriers for clinical testing of safety tested, repurposed small molecule therapeutics are a potentially economical and effective path forward to fill the pre-referral gap in the setting of snakebite.

OBJECTIVE: To implement and evaluate a regional prepregnancy care program in women with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: Prepregnancy care was promoted among patients and health professionals and delivered across 10 regional maternity units. A prospective cohort study of 680 pregnancies in women with type 1 and type 2 diabetes was performed. Primary outcomes were adverse pregnancy outcome (congenital malformation, stillbirth, or neonatal death), congenital malformation, and indicators of pregnancy preparation (5 mg folic acid, gestational age, and A1C). Comparisons were made with a historical cohort (n = 613 pregnancies) from the same units during 1999-2004. RESULTS: A total of 181 (27%) women attended, and 499 women (73%) did not attend prepregnancy care. Women with prepregnancy care presented earlier (6.7 vs. 7.7 weeks; P < 0.001), were more likely to take 5 mg preconception folic acid (88.2 vs. 26.7%; P < 0.0001) and had lower A1C levels (A1C 6.9 vs. 7.6%; P < 0.0001). They had fewer adverse pregnancy outcomes (1.3 vs. 7.8%; P = 0.009). Multivariate logistic regression confirmed that in addition to glycemic control, lack of prepregnancy care was independently associated with adverse outcome (odds ratio 0.2 [95% CI 0.05-0.89]; P = 0.03). Compared with 1999-2004, folic acid supplementation increased (40.7 vs. 32.5%; P = 0.006) and congenital malformations decreased (4.3 vs. 7.3%; P = 0.04). CONCLUSIONS: Regional prepregnancy care was associated with improved pregnancy preparation and reduced risk of adverse pregnancy outcome in type 1 and type 2 diabetes. Prepregnancy care had benefits beyond improved glycemic control and was a stronger predictor of pregnancy outcome than maternal obesity, ethnicity, or social disadvantage.

A theory of the elastic behaviour of thin rubber films is developed to describe inflation of pressure-limited tracheal tube cuffs (a) outside and (b) inside rigid cylindrical model tracheas. At each stage, assumptions and results were successfully checked against experiment. The theory predicts cylinder wall versus intracuff pressure. This allows, for any suitable cuff (of which there are many), the determination of a single intracuff pressure that ensures a satisfactory seal, for any diameter within the human adult range, the wall pressure staying below some chosen safety limit.

BACKGROUND: Emergency intubation has been widely advocated as a life saving procedure in severe acute illness and injury associated with real or potential compromises to the patient's airway and ventilation. However, some initial data have suggested a lack of observed benefit. OBJECTIVES: To determine in acutely ill and injured patients who have real or anticipated problems in maintaining an adequate airway whether emergency endotracheal intubation, as opposed to other airway management techniques, improves the outcome in terms of survival, degree of disability at discharge or length of stay and complications occurring in hospital. SEARCH STRATEGY: We searched the Cochrane Injuries Group Specialised Register (December 2006), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2006, Issue 4), MEDLINE (1950 to November 2006), EMBASE (1980 to week 50, December 2006), National Research Register (Issue 4, 2006), CINAHL (1980 to December 2006), BIDS (to December 2006) and ICNARC (to December 2006). We also examined reference lists of articles for relevant material and contacted experts in the field. Non-English language publications were searched for and examined. SELECTION CRITERIA: All randomised (RCTs) or controlled clinical trials involving the emergency use of endotracheal intubation in the injured or acutely ill patient were examined. DATA COLLECTION AND ANALYSIS: The full texts of 452 studies were reviewed independently by two authors using a standard form. Where the review authors felt a study may be relevant for inclusion in the final review or disagreed, the authors examined the study and a collective decision was made regarding its inclusion or exclusion from the review. The results were not combined in a meta-analysis due to the heterogeneity of patients, practitioners and alternatives to intubation that were used. MAIN RESULTS: We identified three eligible RCTs carried out in urban environments. Two trials involved adults with non-traumatic out-of-hospital cardiac arrest. One of these trials found a non-significant survival disadvantage in patients randomised to receive a physician-operated intubation versus a combi-tube (RR 0.44, 95% CI 0.09 to 1.99). The second trial detected a non-significant survival disadvantage in patients randomised to paramedic intubation versus an oesophageal gastric airway (RR 0.86, 95% CI 0.39 to 1.90). The third included study was a trial of children requiring airway intervention in the prehospital environment. The results indicated no difference in survival (OR 0.82, 95% CI 0.61 to 1.11) or neurologic outcome (OR 0.87, 95% CI 0.62 to 1.22) between paramedic intubation versus bag-valve-mask ventilation and later hospital intubation by emergency physicians; however, only 42% of the children randomised to paramedic endotracheal intubation actually received it. AUTHORS' CONCLUSIONS: The efficacy of emergency intubation as currently practised has not been rigorously studied. The skill level of the operator may be key in determining efficacy. In non-traumatic cardiac arrest, it is unlikely that intubation carries the same life saving benefit as early defibrillation and bystander cardiopulmonary resuscitation (CPR). In trauma and paediatric patients, the current evidence base provides no imperative to extend the practice of prehospital intubation in urban systems. It would be ethical and pertinent to initiate a large, high quality randomised trial comparing the efficacy of competently practised emergency intubation with basic bag-valve-mask manoeuvres (BVM) in urban adult out-of-hospital non-traumatic cardiac arrest.

Our aim was to judge the influence of preoperative psychological disturbance on the outcome of lumbar discectomy. We evaluated 66 patients, before and after operation, using a self-administered questionnaire. Disability was assessed using the Oswestry disability index and psychological disturbance the Distress and Risk Assessment Method (DRAM) score. Patients were classified as normal, at risk or distressed, and the outcome of surgery in the three groups was compared at a follow-up of six months. The mean self-reported preoperative disability was significantly higher in those with psychological disturbance. A total of 54 patients (82%) returned completed postoperative questionnaires. Postoperative disability scores at six months were not significantly different in the three risk groups. Psychological disturbance improved after surgery. Our study suggests that the early outcome of lumbar discectomy is not affected by preoperative psychological disturbance. We conclude that a patient with a symptomatic prolapsed intervertebral disc should not be denied surgery on the basis of preoperative psychological assessment.

BACKGROUND: Haemorrhoids are variceal dilatations of the anal and perianal venous plexus and often develop secondary to the persistently elevated venous pressure within the haemorrhoidal plexus (Kumar 2005). Phlebotonics are a heterogenous class of drugs consisting of plant extracts (i.e. flavonoids) and synthetic compounds (i.e. calcium dobesilate). Although their precise mechanism of action has not been fully established, they are known to improve venous tone, stabilize capillary permeability and increase lymphatic drainage. They have been used to treat a variety of conditions including chronic venous insufficiency, lymphoedema and haemorrhoids.Numerous trials assessing the effect of phlebotonics in treating the symptoms and signs of haemorrhoidal disease suggest that there is a potential benefit. OBJECTIVES: The aim of this review was to investigate the efficacy of phlebotonics in alleviating the signs, symptoms and severity of haemorrhoidal disease and verify their effect post-haemorrhoidectomy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library 2011 issue 9 , MEDLINE (1950 to September 2011) and EMBASE (1974 to September 2011). SELECTION CRITERIA: Only randomised controlled trials evaluating the use of phlebotonics in treating haemorrhoidal disease were used. No cross-over or cluster-randomized trials were included for analysis and any trial which had a quasi-random method of allocation was excluded. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data and analysed the eligibility of the data for inclusion. Disagreements were resolved by meaningful discussion. MAIN RESULTS: We considered twenty-four studies for inclusion in the final analysis. Twenty of these studies (enrolling a total of 2344 participants) evaluated the use of phlebotonics versus a control intervention. One of these twenty studies evaluated the use of phlebotonics with a medical intervention and another study with rubber band ligation.The remaining four studies included two which compared different forms of phlebotonics with each other, one study which evaluated phlebotonics with a medical intervention and one study which compared the use of phlebotonics with infrared photocoagulation. Eight studies were excluded for various reasons including poor methodological quality.Phlebotonics demonstrated a statistically significant beneficial effect for the outcomes of pruritus (OR 0.23; 95% CI 0.07 to 0.79) (P=0.02), bleeding (OR 0.12; 95% CI 0.04 to 0.37) (P=0.0002), bleeding post-haemorrhoidectomy (OR 0.18; 95% 0.06 to 0.58)(P=0.004), discharge and leakage (OR 0.12; 95% CI 0.04 to 0.42) (P=0.0008) and overall symptom improvement (OR 15.99 95% CI 5.97 to 42.84) (P< 0.00001), in comparison with a control intervention. Although beneficial they did not show a statistically significant effect compared with a control intervention for pain (OR 0.11; 95% CI 0.01 to 1.11) (P=0.06), pain scores post-haemorrhoidectomy (SMD -1.04; 95% CI -3.21 to 1.12 ) (P= 0.35) or post-operative analgesic consumption (OR 0.54; 95% CI 0.30 to 0.99)(P=0.05). AUTHORS' CONCLUSIONS: The evidence suggests that there is a potential benefit in using phlebotonics in treating haemorrhoidal disease as well as a benefit in alleviating post-haemorrhoidectomy symptoms. Outcomes such as bleeding and overall symptom improvement show a statistically significant beneficial effect and there were few concerns regarding their overall safety from the evidence presented in the clinical trials.However methodological limitations were encountered. In order to enhance our conclusion further, more robust clinical trials which take into account these limitations will need to be performed in the future.

This study prospectively evaluated the outcome of manipulation under anaesthesia and hydrodilatation as treatments for adhesive capsulitis. A total of 36 patients (38 shoulders) were randomised to receive either method, with all patients being treated in stage II of the disease process. The mean age of the patients was 55.2 years (44 to 70) and the mean duration of symptoms was 33.7 weeks (12 to 76). Eighteen shoulders (17 patients) underwent manipulation under anaesthesia and 20 (19 patients) had hydrodilatation. There were three insulin-dependent diabetics in each group. The mean visual analogue score in the manipulation under anaesthesia group was 5.7 (3 to 8.5; n = 18) before treatment, 4.7 (0 to 8.5; n = 16) at two months (paired t-test p = 0.02), and 2.7 (0 to 9; n = 16) at six months (paired t-test, p = 0.0006). The mean score in the hydrodilatation group was 6.1 (4 to 10; n = 20) before treatment, 2.4 (0 to 8; n = 18) at two months (paired t-test, p = 0.001), and 1.7 (0 to 7; n = 18) at six months (paired t-test, p = 0.0006). The visual analogue scores in the hydrodilatation group were significantly better than in the manipulation under anaesthesia group over the six-month follow-up period (p < 0.0001). The mean Constant score in those manipulated was 36 (26 to 66) before treatment, 58.5 (24 to 90) at two months (paired t-test, p = 0.001) and 59.5 (23 to 85) at six months (paired t-test, p = 0.0006). In the hydrodilatation group it was 28.8 (18 to 55) before treatment, 57.4 (17 to 80) at two months (paired t-test, p = 0.0004) and 65.9 (28 to 92) at six months (paired t-test, p = 0.0005). The Constant scores in the hydrodilatation group were significantly better than in the manipulated group over the six-month period of follow-up (p = 0.02). The range of movement improved in all patients over the six months, but was not significantly different between the groups. At the final follow-up, 94% of patients (17 of 18) were satisfied or very satisfied after hydrodilatation compared with 81% (13 of 16) of those receiving a manipulation. Most of our patients were treated successfully, but those undergoing hydrodilatation did better than those who were manipulated.

The first human case of a homozygous molecular defect in the gene encoding insulin-like growth factor I (IGF-I) is described. The patient was a 15-year-old boy from a consanguineous pedigree who presented with severe intrauterine growth failure, sensorineural deafness and mild mental retardation. Endocrine evaluation of the growth hormone (GH)--IGF-I axis revealed elevated GH secretion, undetectable serum IGF-I and normal serum IGF-binding protein-3, acid-labile subunit, and GH-binding activity. Analysis of the IGF-I gene revealed a homozygous partial IGF-I gene deletion involving exons 4 and 5, which encodes a severely truncated mature IGF-I peptide. This patient demonstrates that complete disruption of the IGF-I gene in man is compatible with life, and indicates a major role for IGF-I in human fetal growth. In addition, his neurological abnormalities suggest that IGF-I may be involved in central nervous system development.

BACKGROUND: There is currently an unmet clinical need to develop better pharmacological treatments to improve glucose handling in Type II Diabetes patients with obesity. To this end, determining the effect of obesity-associated adipokines on skeletal muscle insulin sensitivity has emerged as an important area of drug discovery research. This review draws together the data on the functional role of adipokines on skeletal muscle insulin signalling, highlights several understudied novel adipokines and provides a perspective on the direction of future research. MAIN BODY: The adipokines leptin, resistin, visfatin and adiponectin have all been shown to affect skeletal muscle insulin sensitivity by impacting on the activity of components within insulin signalling pathways, affecting GLUT4 translocation and modulating insulin-mediated skeletal muscle glucose uptake. Furthermore, proteomic analysis of the adipose tissue secretome has recently identified several novel adipokines including vaspin, chemerin and pref-1 that are associated with obesity and insulin resistance in humans and functionally impact on insulin signalling pathways. However, predominantly, these functional findings are the result of studies in rodents, with in vitro studies utilising either rat L6 or murine C2C12 myoblasts and/or myotubes. Despite the methodology to isolate and culture human myoblasts and to differentiate them into myotubes being established, the use of human muscle in vitro models for the functional validation of adipokines on skeletal muscle insulin sensitivity is limited. CONCLUSION: Understanding the mechanism of action and function of adipokines in mediating insulin sensitivity in skeletal muscle may lead to the development of novel therapeutics for patients with type 2 diabetes. However, to date, studies conducted in human skeletal muscle cells and tissues are limited. Such human in vitro studies should be prioritised in order to reduce the risk of candidate drugs failing in the clinic due to the assumption that rodent skeletal muscle target validation studies will to translate to human.

The tracheal wall pressure (TWP) exerted by a tracheal tube cuff should normally be kept between 20 and 30 cmH2O. This protects against mucosal injury whilst allowing ventilation without an audible air leak [1]. The Portex Soft Seal high-volume low-pressure (HVLP) cuff has a working intracuff pressure of 30 cmH2O, providing a safe TWP of the same value because there is no tension in the cuff wall material. There are, however, folds within the cuff wall that allow passage of subglottic fluid to the tracheobronchial tree below, increasing the risk of ventilator-associated pneumonia [2]. The Lotrach endotracheal tube was designed to prevent this leakage at an equivalent TWP to that of correctly inflated HVLP cuffs [3]. Each Lotrach cuff is individually calibrated to transmit only 30 cmH2O to the tracheal wall, yet because of the lack of folds in the cuff wall it has been shown to prevent of aspiration of subglottic contents [4]. Although extensively tested in benchtop models and pig tracheas, we wished to demonstrate that the Lotrach cuff had an identical sealing pressure, and therefore TWP, as the HVLP cuff in normal clinical practice.

Primary infection with drug-resistant HIV-1 is well documented. We have followed up patients infected with such viruses to determine the stability of resistance-associated mutations. Fourteen patients who experienced primary infection with genotypic evidence of resistance were followed for up to 3 years. Drug resistance-associated mutations persisted over time in most patients studied. In particular, M41L, T69N, K103N, and T215 variants within reverse transcriptase (RT) and multidrug resistance demonstrated little reversion to wild-type virus. By contrast, Y181C and K219Q in RT, occurring alone, disappeared within 25 and 9 months, respectively. Multidrug resistance in 2 patients was found to be stable for up to 18 months, the maximum period studied. We conclude that certain resistance-associated mutations are highly stable and these data support the recommendation that all new HIV diagnoses in areas where primary resistance may occur should undergo genotyping irrespective of whether the date of seroconversion is known.