Northampton General Hospital

ABSTRACT Background Coronavirus disease 2019 (COVID-19) is associated with diffuse lung damage. Corticosteroids may modulate immune-mediated lung injury and reducing progression to respiratory failure and death. Methods The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, adaptive, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19. We report the preliminary results for the comparison of dexamethasone 6 mg given once daily for up to ten days vs. usual care alone. The primary outcome was 28-day mortality. Results 2104 patients randomly allocated to receive dexamethasone were compared with 4321 patients concurrently allocated to usual care. Overall, 454 (21.6%) patients allocated dexamethasone and 1065 (24.6%) patients allocated usual care died within 28 days (age-adjusted rate ratio [RR] 0.83; 95% confidence interval [CI] 0.74 to 0.92; P<0.001). The proportional and absolute mortality rate reductions varied significantly depending on level of respiratory support at randomization (test for trend p<0.001): Dexamethasone reduced deaths by one-third in patients receiving invasive mechanical ventilation (29.0% vs. 40.7%, RR 0.65 [95% CI 0.51 to 0.82]; p<0.001), by one-fifth in patients receiving oxygen without invasive mechanical ventilation (21.5% vs. 25.0%, RR 0.80 [95% CI 0.70 to 0.92]; p=0.002), but did not reduce mortality in patients not receiving respiratory support at randomization (17.0% vs. 13.2%, RR 1.22 [95% CI 0.93 to 1.61]; p=0.14). Conclusions In patients hospitalized with COVID-19, dexamethasone reduced 28-day mortality among those receiving invasive mechanical ventilation or oxygen at randomization, but not among patients not receiving respiratory support. Trial registrations The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov ( NCT04381936 ). Funding Medical Research Council and National Institute for Health Research (Grant ref: MC_PC_19056).

OBJECTIVE: To evaluate the effectiveness of a structured group education programme on biomedical, psychosocial, and lifestyle measures in people with newly diagnosed type 2 diabetes. DESIGN: Multicentre cluster randomised controlled trial in primary care with randomisation at practice level. SETTING: 207 general practices in 13 primary care sites in the United Kingdom. PARTICIPANTS: 824 adults (55% men, mean age 59.5 years). INTERVENTION: A structured group education programme for six hours delivered in the community by two trained healthcare professional educators compared with usual care. MAIN OUTCOME MEASURES: Haemoglobin A(1c) levels, blood pressure, weight, blood lipid levels, smoking status, physical activity, quality of life, beliefs about illness, depression, and emotional impact of diabetes at baseline and up to 12 months. MAIN RESULTS: Haemoglobin A(1c) levels at 12 months had decreased by 1.49% in the intervention group compared with 1.21% in the control group. After adjusting for baseline and cluster, the difference was not significant: 0.05% (95% confidence interval -0.10% to 0.20%). The intervention group showed a greater weight loss: -2.98 kg (95% confidence interval -3.54 to -2.41) compared with 1.86 kg (-2.44 to -1.28), P=0.027 at 12 months. The odds of not smoking were 3.56 (95% confidence interval 1.11 to 11.45), P=0.033 higher in the intervention group at 12 months. The intervention group showed significantly greater changes in illness belief scores (P=0.001); directions of change were positive indicating greater understanding of diabetes. The intervention group had a lower depression score at 12 months: mean difference was -0.50 (95% confidence interval -0.96 to -0.04); P=0.032. A positive association was found between change in perceived personal responsibility and weight loss at 12 months (beta=0.12; P=0.008). CONCLUSION: A structured group education programme for patients with newly diagnosed type 2 diabetes resulted in greater improvements in weight loss and smoking cessation and positive improvements in beliefs about illness but no difference in haemoglobin A(1c) levels up to 12 months after diagnosis. TRIAL REGISTRATION: Current Controlled Trials ISRCTN17844016 [controlled-trials.com].

The extent to which the oral glucose tolerance test can be used to estimate insulin secretion and insulin resistance has been evaluated by comparing glucose and insulin concentrations during an oral glucose tolerance test with specific measurements of insulin secretion and insulin resistance in 85 normoglycaemic subjects and 23 subjects with impaired glucose tolerance (IGT). Insulin secretion was measured by the first phase insulin response to intravenous glucose and insulin resistance by the insulin tolerance test which measures the decline of plasma glucose after the injection of a bolus of insulin. The best measure of insulin secretion was the ratio of the 30 min increment in insulin concentration to the 30 min increment in glucose concentration following oral glucose loading. This correlated with the first phase insulin release following intravenous glucose (r = 0.61, p < 0.001) but not insulin resistance (r = -0.05, p > 0.05). Insulin resistance could be estimated by the fasting insulin, proinsulin, or split proinsulin concentrations. However, fasting split proinsulin appeared to discriminate best between insulin resistance (r = -0.53, p < 0.001) and insulin secretion (r = 0.07, p > 0.05). Relative insulin resistance estimated by homeostasis model assessment (HOMA) also correlated well with insulin resistance (r = -0.57, p < 0.001) but not insulin secretion (r = 0.01, p > 0.05). We conclude that the oral glucose tolerance test can be used to derive estimates of the relative roles of insulin secretion and insulin resistance in population studies of glucose tolerance.

The Obstetric Anaesthetists' Association and Difficult Airway Society have developed the first national obstetric guidelines for the safe management of difficult and failed tracheal intubation during general anaesthesia. They comprise four algorithms and two tables. A master algorithm provides an overview. Algorithm 1 gives a framework on how to optimise a safe general anaesthetic technique in the obstetric patient, and emphasises: planning and multidisciplinary communication; how to prevent the rapid oxygen desaturation seen in pregnant women by advocating nasal oxygenation and mask ventilation immediately after induction; limiting intubation attempts to two; and consideration of early release of cricoid pressure if difficulties are encountered. Algorithm 2 summarises the management after declaring failed tracheal intubation with clear decision points, and encourages early insertion of a (preferably second-generation) supraglottic airway device if appropriate. Algorithm 3 covers the management of the 'can't intubate, can't oxygenate' situation and emergency front-of-neck airway access, including the necessity for timely perimortem caesarean section if maternal oxygenation cannot be achieved. Table 1 gives a structure for assessing the individual factors relevant in the decision to awaken or proceed should intubation fail, which include: urgency related to maternal or fetal factors; seniority of the anaesthetist; obesity of the patient; surgical complexity; aspiration risk; potential difficulty with provision of alternative anaesthesia; and post-induction airway device and airway patency. This decision should be considered by the team in advance of performing a general anaesthetic to make a provisional plan should failed intubation occur. The table is also intended to be used as a teaching tool to facilitate discussion and learning regarding the complex nature of decision-making when faced with a failed intubation. Table 2 gives practical considerations of how to awaken or proceed with surgery. The background paper covers recommendations on drugs, new equipment, teaching and training.

BACKGROUND: Spasticity is a disabling complication of multiple sclerosis, affecting many patients with the condition. We report the first Phase 3 placebo-controlled study of an oral antispasticity agent to use an enriched study design. METHODS: A 19-week follow-up, multicentre, double-blind, randomized, placebo-controlled, parallel-group study in subjects with multiple sclerosis spasticity not fully relieved with current antispasticity therapy. Subjects were treated with nabiximols, as add-on therapy, in a single-blind manner for 4weeks, after which those achieving an improvement in spasticity of ≥20% progressed to a 12-week randomized, placebo-controlled phase. RESULTS: Of the 572 subjects enrolled, 272 achieved a ≥20% improvement after 4weeks of single-blind treatment, and 241 were randomized. The primary end-point was the difference between treatments in the mean spasticity Numeric Rating Scale (NRS) in the randomized, controlled phase of the study. Intention-to-treat (ITT) analysis showed a highly significant difference in favour of nabiximols (P=0.0002). Secondary end-points of responder analysis, Spasm Frequency Score, Sleep Disturbance NRS Patient, Carer and Clinician Global Impression of Change were all significant in favour of nabiximols. CONCLUSIONS: The enriched study design provides a method of determining the efficacy and safety of nabiximols in a way that more closely reflects proposed clinical practice, by limiting exposure to those patients who are likely to benefit from it. Hence, the difference between active and placebo should be a reflection of efficacy and safety in the population intended for treatment.

OBJECTIVES: To assess the efficacy of a cannabis-based medicine (CBM) in the treatment of pain due to rheumatoid arthritis (RA). METHODS: We compared a CBM (Sativex) with placebo in a randomized, double-blind, parallel group study in 58 patients over 5 weeks of treatment. The CBM was administered by oromucosal spray in the evening and assessments were made the following morning. Efficacy outcomes assessed were pain on movement, pain at rest, morning stiffness and sleep quality measured by a numerical rating scale, the Short-Form McGill Pain Questionnaire (SF-MPQ) and the DAS28 measure of disease activity. RESULTS: Seventy-five patients were screened and 58 met the eligibility criteria. Thirty-one were randomized to the CBM and 27 to placebo. Mean (S.D.) daily dose achieved in the final treatment week was 5.4 (0.84) actuations for the CBM and 5.3 (1.18) for placebo. In comparison with placebo, the CBM produced statistically significant improvements in pain on movement, pain at rest, quality of sleep, DAS28 and the SF-MPQ pain at present component. There was no effect on morning stiffness but baseline scores were low. The large majority of adverse effects were mild or moderate, and there were no adverse effect-related withdrawals or serious adverse effects in the active treatment group. CONCLUSIONS: In the first ever controlled trial of a CBM in RA, a significant analgesic effect was observed and disease activity was significantly suppressed following Sativex treatment. Whilst the differences are small and variable across the population, they represent benefits of clinical relevance and show the need for more detailed investigation in this indication.

OBJECTIVE: To assess the effect on time to diagnosis of recurrence and on quality of life of transferring primary responsibility for follow up of women with breast cancer in remission from hospital to general practice. DESIGN: Randomised controlled trial with 18 month follow up in which women received routine follow up either in hospital or in general practice. SUBJECTS AND SETTING: 296 women with breast cancer in remission receiving regular follow up care at district general hospitals in England. MAIN OUTCOME MEASURES: Time between first presentation of symptoms to confirmation of recurrence; quality of life measured by specific dimensions of the SF-36 schedule, the EORTC symptom scale, and hospital anxiety and depression scale. RESULTS: Most recurrences (18/26, 69%) presented as interval events, and almost half (7/16, 44%) of the recurrences in the hospital group presented first to general practice. The median time to hospital confirmation of recurrence was 21 days in the hospital group (range 1-376 days) and 22 days in the general practice group (range 4-64). The differences between groups in the change in SF-36 mean scores from baseline were small: -1.8 (95% confidence interval -7.2 to 3.5) for social functioning, 0.5 (-4.1 to 5.1) for mental health, and 0.6 (-3.6 to 4.8) for general health perception. The change from baseline in the mean depression score was higher in the general practice group at the mid-trial assessment (difference 0.6, 0.1 to 1.2) but there was no significant difference between groups in the anxiety score or the EORTC scales. CONCLUSION: General practice follow up of women with breast cancer in remission is not associated with increase in time to diagnosis, increase in anxiety, or deterioration in health related quality of life. Most recurrences are detected by women as interval events and present to the general practitioner, irrespective of continuing hospital follow up.

INTRODUCTION: The concept of using a mesh to repair hernias was introduced over 50 years ago. Mesh repair is now standard in most countries and widely accepted as superior to primary suture repair. As a result, there has been a rapid growth in the variety of meshes available and choosing the appropriate one can be difficult. This article outlines the general properties of meshes and factors to be considered when selecting one. MATERIALS AND METHODS: We performed a search of the medical literature from 1950 to 1 May 2009, as indexed by Medline, using the PubMed search engine (www.pubmed.gov). To capture all potentially relevant articles with the highest degree of sensitivity, the search terms were intentionally broad. We used the following terms: 'mesh, pore size, strength, recurrence, complications, lightweight, properties'. We also hand-searched the bibliographies of relevant articles and product literature to identify additional pertinent reports. RESULTS AND CONCLUSIONS: The most important properties of meshes were found to be the type of filament, tensile strength and porosity. These determine the weight of the mesh and its biocompatibility. The tensile strength required is much less than originally presumed and light-weight meshes are thought to be superior due to their increased flexibility and reduction in discomfort. Large pores are also associated with a reduced risk of infection and shrinkage. For meshes placed in the peritoneal cavity, consideration should also be given to the risk of adhesion formation. A variety of composite meshes have been promoted to address this, but none appears superior to the others. Finally, biomaterials such as acellular dermis have a place for use in infected fields but have yet to prove their worth in routine hernia repair.

Symptoms relating to spasticity are common in multiple sclerosis (MS) and can be difficult to treat. We have investigated the efficacy, safety and tolerability of a standardized oromucosal whole plant cannabis-based medicine (CBM) containing delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD), upon spasticity in MS. A total of 189 subjects with definite MS and spasticity were randomized to receive daily doses of active preparation (n = 124) or placebo (n = 65) in a double blind study over 6 weeks. The primary endpoint was the change in a daily subject-recorded Numerical Rating Scale of spasticity. Secondary endpoints included a measure of spasticity (Ashworth Score) and a subjective measure of spasm. The primary efficacy analysis on the intention to treat (ITT) population (n = 184) showed the active preparation to be significantly superior (P = 0.048). Secondary efficacy measures were all in favour of active preparation but did not achieve statistical significance. The responder analysis favoured active preparation, 40% of subjects achieved >30% benefit (P = 0.014). Eight withdrawals were attributed to adverse events (AEs); six were on active preparation and two on placebo. We conclude that this CBM may represent a useful new agent for treatment of the symptomatic relief of spasticity in MS.

AIMS: To determine the efficacy and patient perception of various transfer procedures from paediatric to adult diabetes services. METHODS: Comparison between four districts in the Oxford Region employing different transfer methods, by retrospective study of case records and interviews of patients recently transferred from paediatric diabetes clinics. The main outcome measures were age at transfer, clinic attendance rates, HbA1c measurements and questionnaire responses. RESULTS: Two hundred and twenty-nine subjects (57% males) > 18 years old in 1998 and diagnosed with Type 1 diabetes < 16 years of age between 1985 and 1995, identified from the regional diabetes register. The notes audit was completed for 222 (97%) and 164 (72%) were interviewed by a single research nurse. Mean age at transfer was 17.9 years (range 13.3-22.4 years). Few young people were lost to follow-up at the point of transfer. There was a high rate of clinic attendance (at least 6 monthly) 2 years pretransfer (94%), but this declined to 57% 2 years post-transfer (P < 0.0005). There was large interdistrict variation in clinic attendance 2 years post-transfer (29% to 71%); higher rates were seen in districts where young people had the opportunity to meet the adult diabetes consultant prior to transfer. The importance of this opportunity was confirmed by questionnaire responses on interview. CONCLUSIONS: Adolescence is a vulnerable period for patients with diabetes. This regional survey demonstrated a marked decline in clinic attendance around the time of transition from paediatric to adult services. The reasons are complex, but mode of transfer may be an important factor.

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.

Chondral injuries involving the knee are common. In a recent study of 993 consecutive arthroscopies scored using the International Cartilage Repair Society (ICRS) knee evaluation form,[1][1] articular cartilage pathology was found in 66% of patients, while 11% had localised, full-thickness lesions

ABSTRACT Background Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (COVID-19) on the basis of in vitro activity, uncontrolled data, and small randomized studies. Methods The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19. We report the preliminary results for the comparison of hydroxychloroquine vs. usual care alone. The primary outcome was 28-day mortality. Results 1561 patients randomly allocated to receive hydroxychloroquine were compared with 3155 patients concurrently allocated to usual care. Overall, 418 (26.8%) patients allocated hydroxychloroquine and 788 (25.0%) patients allocated usual care died within 28 days (rate ratio 1.09; 95% confidence interval [CI] 0.96 to 1.23; P=0.18). Consistent results were seen in all pre-specified subgroups of patients. Patients allocated to hydroxychloroquine were less likely to be discharged from hospital alive within 28 days (60.3% vs. 62.8%; rate ratio 0.92; 95% CI 0.85-0.99) and those not on invasive mechanical ventilation at baseline were more likely to reach the composite endpoint of invasive mechanical ventilation or death (29.8% vs. 26.5%; risk ratio 1.12; 95% CI 1.01-1.25). There was no excess of new major cardiac arrhythmia. Conclusions In patients hospitalized with COVID-19, hydroxychloroquine was not associated with reductions in 28-day mortality but was associated with an increased length of hospital stay and increased risk of progressing to invasive mechanical ventilation or death. Funding Medical Research Council and NIHR (Grant ref: MC_PC_19056). Trial registrations The trial is registered with ISRCTN (50189673) and clinicaltrials.gov ( NCT04381936 ).

BACKGROUND: Silver-Russell syndrome (SRS) is characterised by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, triangular face and asymmetry. Maternal uniparental disomy (mUPD) of chromosome 7 and hypomethylation of the imprinting control region (ICR) 1 on chromosome 11p15 are found in 5-10% and up to 60% of patients with SRS, respectively. As many features are non-specific, diagnosis of SRS remains difficult. Studies of patients in whom the molecular diagnosis is confirmed therefore provide valuable clinical information on the condition. METHODS: A detailed, prospective study of 64 patients with mUPD7 (n=20) or ICR1 hypomethylation (n=44) was undertaken. RESULTS AND CONCLUSIONS: The considerable overlap in clinical phenotype makes it difficult to distinguish these two molecular subgroups reliably. ICR1 hypomethylation was more likely to be scored as 'classical' SRS. Asymmetry, fifth finger clinodactyly and congenital anomalies were more commonly seen with ICR1 hypomethylation, whereas learning difficulties and referral for speech therapy were more likely with mUPD7. Myoclonus-dystonia has been reported previously in one mUPD7 patient. The authors report mild movement disorders in three further cases. No correlation was found between clinical severity and level of ICR1 hypomethylation. Use of assisted reproductive technology in association with ICR1 hypomethylation seems increased compared with the general population. ICR1 hypomethylation was also observed in affected siblings, although recurrence risk remains low in the majority of cases. Overall, a wide range of severity was observed, particularly with ICR1 hypomethylation. A low threshold for investigation of patients with features suggestive, but not typical, of SRS is therefore recommended.

BACKGROUND: Estimates of children and adolescents with disabilities worldwide are needed to inform global intervention under the disability-inclusive provisions of the Sustainable Development Goals. We sought to update the most widely reported estimate of 93 million children <15 years with disabilities from the Global Burden of Disease Study 2004. METHODS: We analyzed Global Burden of Disease Study 2017 data on the prevalence of childhood epilepsy, intellectual disability, and vision or hearing loss and on years lived with disability (YLD) derived from systematic reviews, health surveys, hospital and claims databases, cohort studies, and disease-specific registries. Point estimates of the prevalence and YLD and the 95% uncertainty intervals (UIs) around the estimates were assessed. RESULTS: Globally, 291.2 million (11.2%) of the 2.6 billion children and adolescents (95% UI: 249.9-335.4 million) were estimated to have 1 of the 4 specified disabilities in 2017. The prevalence of these disabilities increased with age from 6.1% among children aged <1 year to 13.9% among adolescents aged 15 to 19 years. A total of 275.2 million (94.5%) lived in low- and middle-income countries, predominantly in South Asia and sub-Saharan Africa. The top 10 countries accounted for 62.3% of all children and adolescents with disabilities. These disabilities accounted for 28.9 million YLD or 19.9% of the overall 145.3 million (95% UI: 106.9-189.7) YLD from all causes among children and adolescents. CONCLUSIONS: The number of children and adolescents with these 4 disabilities is far higher than the 2004 estimate, increases from infancy to adolescence, and accounts for a substantial proportion of all-cause YLD.

AIM: Although there are numerous studies on the efficacy of enhanced recovery after surgery (ERAS) protocols in reducing length of stay, the long-term compliance to such protocols in routine clinical practice has not been well documented. The aim of this study was to review the published literature on compliance to ERAS in patients undergoing colorectal surgery in routine clinical practice. METHOD: Medline, Embase and PubMed databases were searched to identify studies that focused on compliance to ERAS protocols during routine clinical practice. Fourteen studies fulfilled the inclusion criteria and a total of 19 perioperative ERAS modalities were identified across these studies. RESULTS: None of the studies used all 19 ERAS modalities within their ERAS protocols. Compliance to the various modalities varied considerably between studies and, in general, was poorest during the postoperative period. The use of epidural had the highest compliance (between 67 and 100%), whereas the use of transverse incisions (25%) had the lowest compliance. Length of stay in hospital ranged from 2 to 13 days. Higher compliance was associated with a reduced length of hospital stay. However, reduced length of hospital stay was associated with a high rate of readmission. CONCLUSION: There is significant variation in the components of, as well as in compliance to, ERAS protocols in daily practice. This may contribute to the observed variation between the studies in length of hospital stay. A standardized and practically feasible ERAS protocol should be established in order to improve the implementation and optimal outcome.

This article presents a unified clinical theory that links established facts about the physiology of bone and homeostasis, with those involved in the healing of fractures and the development of nonunion. The key to this theory is the concept that the tissue that forms in and around a fracture should be considered a specific functional entity. This 'bone-healing unit' produces a physiological response to its biological and mechanical environment, which leads to the normal healing of bone. This tissue responds to mechanical forces and functions according to Wolff's law, Perren's strain theory and Frost's concept of the "mechanostat". In response to the local mechanical environment, the bone-healing unit normally changes with time, producing different tissues that can tolerate various levels of strain. The normal result is the formation of bone that bridges the fracture - healing by callus. Nonunion occurs when the bone-healing unit fails either due to mechanical or biological problems or a combination of both. In clinical practice, the majority of nonunions are due to mechanical problems with instability, resulting in too much strain at the fracture site. In most nonunions, there is an intact bone-healing unit. We suggest that this maintains its biological potential to heal, but fails to function due to the mechanical conditions. The theory predicts the healing pattern of multifragmentary fractures and the observed morphological characteristics of different nonunions. It suggests that the majority of nonunions will heal if the correct mechanical environment is produced by surgery, without the need for biological adjuncts such as autologous bone graft. Cite this article: Bone Joint J 2016;98-B:884-91.

BACKGROUND: Guidelines for anal cancer recommend assessment of response at 6-12 weeks after starting treatment. Using data from the ACT II trial, we determined the optimum timepoint to assess clinical tumour response after chemoradiotherapy. METHODS: per day on days 1-4 and 29-32) and radiotherapy (50·4 Gy in 28 daily fractions); and also did a second randomisation after initial therapy to maintenance chemotherapy (fluorouracil and cisplatin) or no maintenance chemotherapy. The primary outcome was complete clinical response (the absence of primary and nodal tumour by clinical examination), in addition to overall survival and progression-free survival from time of randomisation. In this post-hoc analysis, we analysed complete clinical response at three timepoints: 11 weeks from the start of chemoradiotherapy (assessment 1), 18 weeks from the start of chemoradiotherapy (assessment 2), and 26 weeks from the start of chemoradiotherapy (assessment 3) as well as the overall and progression-free survival estimates of patients with complete clinical response or without complete clinical response at each assessment. We analysed both the overall trial population and a subgroup of patients who had attended each of the three assessments by modified intention-to-treat. This study is registered at controlled-trials.com, ISRCTN 26715889. FINDINGS: We enrolled 940 patients from June 4, 2001, until Dec 16, 2008. Complete clinical response was achieved in 492 (52%) of 940 patients at assessment 1 (11 weeks), 665 (71%) of patients at assessment 2 (18 weeks), and 730 (78%) of patients at assessment 3 (26 weeks). 691 patients attended all three assessments and in this subgroup, complete clinical response was reported in 441 (64%) patients at assessment 1, 556 (80%) at assessment 2, and 590 (85%) at assessments 3. 151 (72%) of the 209 patients who had not had a complete clinical response at assessment 1 had a complete clinical response by assessment 3. In the overall trial population of 940 patients, 5 year overall survival in patients who had a clinical response at assessments 1, 2, 3 was 83% (95% CI 79-86), 84% (81-87), and 87% (84-89), respectively and was 72% (66-78), 59% (49-67), and 46% (37-55) for patients who did not have a complete clinical response at assessments 1, 2, 3, respectively. In the subgroup of 691 patients, 5 year overall survival in patients who had a clinical response at assessment 1, 2, 3 was 85% (81-88), 86% (82-88), and 87% (84-90), respectively, and was 75% (68-80), 61% (50-70), and 48% (36-58) for patients who did not have a complete clinical response at assessment 1, 2, 3, respectively. Similarly, progression-free survival in both the overall trial population and the subgroup was longer in patients who had a complete clinical response, compared with patients who did not have a complete clinical response, at all three assessments. INTERPRETATION: Many patients who do not have a complete clinical response when assessed at 11 weeks after commencing chemoradiotherapy do in fact respond by 26 weeks, and the earlier assessment could lead to some patients having unnecessary surgery. Our data suggests that the optimum time for assessment of complete clinical response after chemoradiotherapy for patients with squamous cell carcinoma of the anus is 26 weeks from starting chemoradiotherapy. We suggest that guidelines should be revised to indicate that later assessment is acceptable. FUNDING: Cancer Research UK.

BACKGROUND: Pleural infection is common, and has a >30% major morbidity and mortality-particularly when infection is caused by Gram-negative, Staphylococcus aureus or mixed aerobic pathogens. Standard pleural fluid culture is negative in ∼40% of cases. Culturing pleural fluid in blood culture bottles may increase microbial yield, and is cheap and easy to perform. OBJECTIVES: To determine whether inoculating pleural fluid into blood culture bottles increases the culture positivity of pleural infection over standard laboratory culture, and to assess the optimum volume of inoculum to introduce. METHODS: 62 patients with pleural infection were enrolled. Pairs of aerobic and anaerobic blood culture bottles were inoculated at the bedside with 2, 5 or 10 ml of pleural fluid, and two pleural fluid specimens were sent for standard culture. Pleural fluid from nine control patients was cultured to test for 'false-positive' results. RESULTS: The addition of blood culture bottle culture to standard culture increased the proportion of patients with identifiable pathogens by 20.8% (20/53 (37.7%) to 31/53 (58.5%) (difference 20.8%, 95% CI difference 8.9% to 20.8%, p<0.001)). The second standard culture did not similarly improve the culture positivity (19/49 (38.8%) to 22/49 (44.9%) (difference 6.1%, 95% CI difference -2.5% to 6.1%, p=0.08)). The culture inoculum volume did not influence bacterial isolation frequency. The control fluids were culture negative. CONCLUSIONS: Blood culture bottle culture of infected pleural fluid increases microbial yield when used in addition to standard culture. This technique should be part of routine care.

A trial of antibiotic prophylaxis with cephazolin against postoperative wound sepsis was carried out on 201 patients undergoing routine cholecystectomy. Wound sepsis occurred in 11 out of 65 controls (16.9%), who were not given the drug; two out of 63 patients (3.2%) given a single dose preoperatively; and four out of 73 patients (5.5%) given the single preoperative dose plus a five-day course postoperatively. The difference between the controls and patients given the single preoperative dose was significant.