Liverpool Hospital

IMPORTANCE: The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden. OBJECTIVE: To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019. EVIDENCE REVIEW: The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs). FINDINGS: In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3% (95% UI, 20.3%-32.3%) increase in new cases, a 20.9% (95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4% (1.1%-1.8%) in the low SDI quintile to 5.7% (4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and DALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles. CONCLUSIONS AND RELEVANCE: The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world.

Radiotherapy utilization rates for cancer vary widely internationally. It has previously been suggested that approximately 50% of all cancer patients should receive radiation. However, this estimate was not evidence-based. The aim of this study was to estimate the ideal proportion of new cases of cancer that should receive radiotherapy at least once during the course of their illness based on the best available evidence. An optimal radiotherapy utilization tree was constructed for each cancer based upon indications for radiotherapy taken from evidence-based treatment guidelines. The proportion of patients with clinical attributes that indicated a possible benefit from radiotherapy was obtained by adding epidemiologic data to the radiotherapy utilization tree. The optimal proportion of patients with cancer that should receive radiotherapy was then calculated using TreeAge (TreeAge Software, Williamstown, MA) software. Sensitivity analyses using univariate analysis and Monte Carlo simulations were performed. The proportion of patients with cancer in whom external beam radiotherapy is indicated according to the best available evidence was calculated to be 52%. Monte Carlo analysis indicated that the 95% confidence limits were from 51.7% to 53.1%. The tightness of the confidence interval suggests that the overall estimate is robust. Comparison with actual radiotherapy utilization data suggests a shortfall in actual radiotherapy delivery. This methodology allows comparison of optimal rates with actual rates to identify areas where improvements in the evidence-based use of radiotherapy can be made. It provides valuable data for radiotherapy service planning. Actual rates need to be addressed to ensure better radiotherapy utilization.

PURPOSE: To update the World Society of the Abdominal Compartment Syndrome (WSACS) consensus definitions and management statements relating to intra-abdominal hypertension (IAH) and the abdominal compartment syndrome (ACS). METHODS: We conducted systematic or structured reviews to identify relevant studies relating to IAH or ACS. Updated consensus definitions and management statements were then derived using a modified Delphi method and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidelines, respectively. Quality of evidence was graded from high (A) to very low (D) and management statements from strong RECOMMENDATIONS (desirable effects clearly outweigh potential undesirable ones) to weaker SUGGESTIONS (potential risks and benefits of the intervention are less clear). RESULTS: In addition to reviewing the consensus definitions proposed in 2006, the WSACS defined the open abdomen, lateralization of the abdominal musculature, polycompartment syndrome, and abdominal compliance, and proposed an open abdomen classification system. RECOMMENDATIONS included intra-abdominal pressure (IAP) measurement, avoidance of sustained IAH, protocolized IAP monitoring and management, decompressive laparotomy for overt ACS, and negative pressure wound therapy and efforts to achieve same-hospital-stay fascial closure among patients with an open abdomen. SUGGESTIONS included use of medical therapies and percutaneous catheter drainage for treatment of IAH/ACS, considering the association between body position and IAP, attempts to avoid a positive fluid balance after initial patient resuscitation, use of enhanced ratios of plasma to red blood cells and prophylactic open abdominal strategies, and avoidance of routine early biologic mesh use among patients with open abdominal wounds. NO RECOMMENDATIONS were possible regarding monitoring of abdominal perfusion pressure or the use of diuretics, renal replacement therapies, albumin, or acute component-parts separation. CONCLUSION: Although IAH and ACS are common and frequently associated with poor outcomes, the overall quality of evidence available to guide development of RECOMMENDATIONS was generally low. Appropriately designed intervention trials are urgently needed for patients with IAH and ACS.

BACKGROUND: Treatment of secondary hyperparathyroidism with vitamin D and calcium in patients receiving dialysis is often complicated by hypercalcemia and hyperphosphatemia, which may contribute to cardiovascular disease and adverse clinical outcomes. Calcimimetics target the calcium-sensing receptor and lower parathyroid hormone levels without increasing calcium and phosphorus levels. We report the results of two identical randomized, double-blind, placebo-controlled trials evaluating the safety and effectiveness of the calcimimetic agent cinacalcet hydrochloride. METHODS: Patients who were receiving hemodialysis and who had inadequately controlled secondary hyperparathyroidism despite standard treatment were randomly assigned to receive cinacalcet (371 patients) or placebo (370 patients) for 26 weeks. Once-daily doses were increased from 30 mg to 180 mg to achieve intact parathyroid hormone levels of 250 pg per milliliter or less. The primary end point was the percentage of patients with values in this range during a 14-week efficacy-assessment phase. RESULTS: Forty-three percent of the cinacalcet group reached the primary end point, as compared with 5 percent of the placebo group (P<0.001). Overall, mean parathyroid hormone values decreased 43 percent in those receiving cinacalcet but increased 9 percent in the placebo group (P<0.001). The serum calcium-phosphorus product declined by 15 percent in the cinacalcet group and remained unchanged in the placebo group (P<0.001). Cinacalcet effectively reduced parathyroid hormone levels independently of disease severity or changes in vitamin D sterol dose. CONCLUSIONS: Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism.

Research in artificial intelligence for radiology and radiotherapy has recently become increasingly reliant on the use of deep learning-based algorithms. While the performance of the models which these algorithms produce can significantly outperform more traditional machine learning methods, they do rely on larger datasets being available for training. To address this issue, data augmentation has become a popular method for increasing the size of a training dataset, particularly in fields where large datasets aren't typically available, which is often the case when working with medical images. Data augmentation aims to generate additional data which is used to train the model and has been shown to improve performance when validated on a separate unseen dataset. This approach has become commonplace so to help understand the types of data augmentation techniques used in state-of-the-art deep learning models, we conducted a systematic review of the literature where data augmentation was utilised on medical images (limited to CT and MRI) to train a deep learning model. Articles were categorised into basic, deformable, deep learning or other data augmentation techniques. As artificial intelligence models trained using augmented data make their way into the clinic, this review aims to give an insight to these techniques and confidence in the validity of the models produced.

BACKGROUND: Trials of the efficacy and safety of endovascular thrombectomy in patients with large ischemic strokes have been carried out in limited populations. METHODS: We performed a prospective, randomized, open-label, adaptive, international trial involving patients with stroke due to occlusion of the internal carotid artery or the first segment of the middle cerebral artery to assess endovascular thrombectomy within 24 hours after onset. Patients had a large ischemic-core volume, defined as an Alberta Stroke Program Early Computed Tomography Score of 3 to 5 (range, 0 to 10, with lower scores indicating larger infarction) or a core volume of at least 50 ml on computed tomography perfusion or diffusion-weighted magnetic resonance imaging. Patients were assigned in a 1:1 ratio to endovascular thrombectomy plus medical care or to medical care alone. The primary outcome was the modified Rankin scale score at 90 days (range, 0 to 6, with higher scores indicating greater disability). Functional independence was a secondary outcome. RESULTS: The trial was stopped early for efficacy; 178 patients had been assigned to the thrombectomy group and 174 to the medical-care group. The generalized odds ratio for a shift in the distribution of modified Rankin scale scores toward better outcomes in favor of thrombectomy was 1.51 (95% confidence interval [CI], 1.20 to 1.89; P<0.001). A total of 20% of the patients in the thrombectomy group and 7% in the medical-care group had functional independence (relative risk, 2.97; 95% CI, 1.60 to 5.51). Mortality was similar in the two groups. In the thrombectomy group, arterial access-site complications occurred in 5 patients, dissection in 10, cerebral-vessel perforation in 7, and transient vasospasm in 11. Symptomatic intracranial hemorrhage occurred in 1 patient in the thrombectomy group and in 2 in the medical-care group. CONCLUSIONS: Among patients with large ischemic strokes, endovascular thrombectomy resulted in better functional outcomes than medical care but was associated with vascular complications. Cerebral hemorrhages were infrequent in both groups. (Funded by Stryker Neurovascular; SELECT2 ClinicalTrials.gov number, NCT03876457.).

This review introduces some commonly used methods for assessing the performance of a diagnostic test. The sensitivity, specificity and likelihood ratio of a test are discussed. The uses of the receiver operating characteristic curve and the area under the curve are explained.

Guest editors Guillaume Maurin, Christian Serre, Andrew Cooper and Gérard Férey introduce the Metal–Organic Frameworks and Porous Polymers – Current and Future Challenges issue of <italic>Chemical Society Reviews</italic>.

Synopsis The Geriatric Mental State and a new computerized diagnostic system, AGECAT, are briefly described. A nomenclature for designating cases for epidemiological work is introduced. Concordance between AGECAT and psychiatrists' diagnoses for these studies, hospital and community based (total of 541 subjects), achieved overall kappa values of 0·84 for a psychiatric hospital sample and 0·74 for a community sample. The values for depression and organic illness specifically in these settings were psychiatric hospital 0·80/0·86, and community 0·80/0·88, respectively.

BACKGROUND: Research into the mental health of refugees has burgeoned in recent times, but there is a dearth of studies focusing specifically on the factors associated with psychiatric distress in asylum-seekers who have not been accorded residency status. METHOD: Forty consecutive asylum-seekers attending a community resource centre in Sydney, Australia, were interviewed using structured instruments and questionnaires. RESULTS: Anxiety scores were associated with female gender, poverty, and conflict with immigration officials, while loneliness and boredom were linked with both anxiety and depression. Thirty subjects (79%) had experienced a traumatic event such as witnessing killings, being assaulted, or suffering torture and captivity, and 14 subjects (37%) met full criteria for PTSD. A diagnosis of PTSD was associated with greater exposure to pre-migration trauma, delays in processing refugee applications, difficulties in dealing with immigration officials, obstacles to employment, racial discrimination, and loneliness and boredom. CONCLUSIONS: Although based on correlational data derived from'a convenient' sample, our findings raise the possibility that current procedures for dealing with asylum-seekers may contribute to high levels of stress and psychiatric symptoms in those who have been previously traumatised.

BACKGROUND: Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use. The short-term mortality among patients with severe disease exceeds 30%. Prednisolone and pentoxifylline are both recommended for the treatment of severe alcoholic hepatitis, but uncertainty about their benefit persists. METHODS: We conducted a multicenter, double-blind, randomized trial with a 2-by-2 factorial design to evaluate the effect of treatment with prednisolone or pentoxifylline. The primary end point was mortality at 28 days. Secondary end points included death or liver transplantation at 90 days and at 1 year. Patients with a clinical diagnosis of alcoholic hepatitis and severe disease were randomly assigned to one of four groups: a group that received a pentoxifylline-matched placebo and a prednisolone-matched placebo, a group that received prednisolone and a pentoxifylline-matched placebo, a group that received pentoxifylline and a prednisolone-matched placebo, or a group that received both prednisolone and pentoxifylline. RESULTS: A total of 1103 patients underwent randomization, and data from 1053 were available for the primary end-point analysis. Mortality at 28 days was 17% (45 of 269 patients) in the placebo-placebo group, 14% (38 of 266 patients) in the prednisolone-placebo group, 19% (50 of 258 patients) in the pentoxifylline-placebo group, and 13% (35 of 260 patients) in the prednisolone-pentoxifylline group. The odds ratio for 28-day mortality with pentoxifylline was 1.07 (95% confidence interval [CI], 0.77 to 1.49; P=0.69), and that with prednisolone was 0.72 (95% CI, 0.52 to 1.01; P=0.06). At 90 days and at 1 year, there were no significant between-group differences. Serious infections occurred in 13% of the patients treated with prednisolone versus 7% of those who did not receive prednisolone (P=0.002). CONCLUSIONS: Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in 28-day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year. (Funded by the National Institute for Health Research Health Technology Assessment program; STOPAH EudraCT number, 2009-013897-42 , and Current Controlled Trials number, ISRCTN88782125 ).

Investigation of contacts of patients with tuberculosis (TB) is a priority for TB control in high-income countries, and is increasingly being considered in resource-limited settings. This review was commissioned for a World Health Organization Expert Panel to develop global contact investigation guidelines. We performed a systematic review and meta-analysis of all studies reporting the prevalence of TB and latent TB infection, and the annual incidence of TB among contacts of patients with TB. After screening 9,555 titles, we included 203 published studies. In 95 studies from low- and middle-income settings, the prevalence of active TB in all contacts was 3.1% (95% CI 2.2-4.4%, I(2)=99.4%), microbiologically proven TB was 1.2% (95% CI 0.9-1.8%, I(2)=95.9%), and latent TB infection was 51.5% (95% CI 47.1-55.8%, I(2)=98.9%). The prevalence of TB among household contacts was 3.1% (95% CI 2.1-4.5%, I(2)=98.8%) and among contacts of patients with multidrug-resistant or extensively drug-resistant TB was 3.4% (95% CI 0.8-12.6%, I(2)=95.7%). Incidence was greatest in the first year after exposure. In 108 studies from high-income settings, the prevalence of TB among contacts was 1.4% (95% CI 1.1-1.8%, I(2)=98.7%), and the prevalence of latent infection was 28.1% (95% CI 24.2-32.4%, I(2)=99.5%). There was substantial heterogeneity among published studies. Contacts of TB patients are a high-risk group for developing TB, particularly within the first year. Children <5 yrs of age and people living with HIV are particularly at risk. Policy recommendations must consider evidence of the cost-effectiveness of various contact tracing strategies, and also incorporate complementary strategies to enhance case finding.

OBJECTIVE: To determine effects of physical activity on depressive symptoms (primary objective), symptoms of schizophrenia, anthropometric measures, aerobic capacity, and quality of life (secondary objectives) in people with mental illness and explore between-study heterogeneity. DATA SOURCES: MEDLINE, Cochrane Controlled Trials Register, PsycINFO, CINAHL, Embase, and the Physiotherapy Evidence Database (PEDro) were searched from earliest record to 2013. STUDY SELECTION: Randomized controlled trials of adults with a DSM-IV-TR, ICD-10, or clinician-confirmed diagnosis of a mental illness other than dysthymia or eating disorders were selected. Interventions included exercise programs, exercise counseling, lifestyle interventions, tai chi, or physical yoga. Study methodological quality and intervention compliance with American College of Sports Medicine (ACSM) guidelines were also assessed. DATA EXTRACTION AND ANALYSIS: Two investigators extracted data. Data were pooled using random-effects meta-analysis. Meta-regression was used to examine sources of between-study heterogeneity. RESULTS: Thirty-nine eligible trials were identified. The primary meta-analysis found a large effect of physical activity on depressive symptoms (n = 20; standardized mean difference (SMD) = 0.80). The effect size in trial interventions that met ACSM guidelines for aerobic exercise did not differ significantly from those that did not meet these guidelines. The effect for trials with higher methodological quality was smaller than that observed for trials with lower methodological quality (SMD = 0.39 vs 1.35); however, the difference was not statistically significant. A large effect was found for schizophrenia symptoms (SMD = 1.0), a small effect was found for anthropometry (SMD = 0.24), and moderate effects were found for aerobic capacity (SMD = 0.63) and quality of life (SMD = 0.64). CONCLUSIONS: Physical activity reduced depressive symptoms in people with mental illness. Larger effects were seen in studies of poorer methodological quality. Physical activity reduced symptoms of schizophrenia and improved anthropometric measures, aerobic capacity, and quality of life among people with mental illness. TRIAL REGISTRATION: PROSPERO registration #CRD42012002012.

This review introduces logistic regression, which is a method for modelling the dependence of a binary response variable on one or more explanatory variables. Continuous and categorical explanatory variables are considered.

BACKGROUND: The main objective of this methodological manuscript was to illustrate the role of using qualitative research in emergency settings. We outline rigorous criteria applied to a qualitative study assessing perceptions and experiences of staff working in Australian emergency departments. METHODS: We used an integrated mixed-methodology framework to identify different perspectives and experiences of emergency department staff during the implementation of a time target government policy. The qualitative study comprised interviews from 119 participants across 16 hospitals. The interviews were conducted in 2015-2016 and the data were managed using NVivo version 11. We conducted the analysis in three stages, namely: conceptual framework, comparison and contrast and hypothesis development. We concluded with the implementation of the four-dimension criteria (credibility, dependability, confirmability and transferability) to assess the robustness of the study, RESULTS: We adapted four-dimension criteria to assess the rigour of a large-scale qualitative research in the emergency department context. The criteria comprised strategies such as building the research team; preparing data collection guidelines; defining and obtaining adequate participation; reaching data saturation and ensuring high levels of consistency and inter-coder agreement. CONCLUSION: Based on the findings, the proposed framework satisfied the four-dimension criteria and generated potential qualitative research applications to emergency medicine research. We have added a methodological contribution to the ongoing debate about rigour in qualitative research which we hope will guide future studies in this topic in emergency care research. It also provided recommendations for conducting future mixed-methods studies. Future papers on this series will use the results from qualitative data and the empirical findings from longitudinal data linkage to further identify factors associated with ED performance; they will be reported separately.

The concept of a Medical Emergency Team was developed in order to rapidly identify and manage seriously ill patients at risk of cardiopulmonary arrest and other high-risk conditions. The aim of this study was to describe the utilization and outcome of Medical Emergency Team interventions over a one-year period at a teaching hospital in South Western Sydney. Data was collected prospectively using a standardized form. Cardiopulmonary resuscitation occurred in 148/522 (28%) calls. Alerting the team using the specific condition criteria occurred in 253/522 (48%) calls and on physiological/pathological abnormality criteria in 121/522 (23%) calls. Survival rate to hospital discharge following cardiopulmonary arrest was low (29%), compared with other medical emergencies (76%).

In Brief Objective: To determine whether skills acquired by simulation-based training transfer to the operative setting. Summary Background Data: The fundamental assumption of simulation-based training is that skills acquired in simulated settings are directly transferable to the operating room, yet little evidence has focused on correlating simulated performance with actual surgical performance. Methods: A systematic search strategy was used to retrieve relevant studies. Inclusion of articles was determined using a predetermined protocol, independent assessment by 2 reviewers, and a final consensus decision. Only studies that reported on the use of simulation-based training for surgical skills training, and the transferability of these skills to the operative setting, were included. Results: Ten randomized controlled trials and 1 nonrandomized comparative study were included in this review. In most cases, simulation-based training was in addition to normal training programs. Only 1 study compared simulation-based training with patient-based training. For laparoscopic cholecystectomy and colonoscopy/sigmoidoscopy, participants who received simulation-based training before undergoing patient-based assessment performed better than their counterparts who did not receive previous simulation training, but improvement was not demonstrated for all measured parameters. Conclusions: Skills acquired by simulation-based training seem to be transferable to the operative setting. The studies included in this review were of variable quality and did not use comparable simulation-based training methodologies, which limited the strength of the conclusions. More studies are required to strengthen the evidence base and to provide the evidence needed to determine the extent to which simulation should become a part of surgical training programs. This article reviews whether skills acquired through simulation training transfer to the operative setting. Study results suggest that trainees who had simulation-based training performed patient-based procedures better than controls, in some but not all measured parameters. More evidence is required to determine the extent to which simulation should become a part of training.

The presence of biofilms in chronic non-healing wounds, has been identified through in vitro model and in vivo animal data. However, human chronic wound studies are under-represented and generally report low sample sizes. For this reason we sought to ascertain the prevalence of biofilms in human chronic wounds by undertaking a systematic review and meta-analysis. Our initial search identified 554 studies from the literature databases (Cochrane Library, Embase, Medline). After removal of duplicates, and those not meeting the requirements of inclusion, nine studies involving 185 chronic wounds met the inclusion criteria. Prevalence of biofilms in chronic wounds was 78.2 % (confidence interval [CI 61.6-89, p<0.002]). The results of our meta-analysis support our clinical assumptions that biofilms are ubiquitous in human chronic non-healing wounds.

There is an incoming tide of concern about the problems of antimicrobial resistance. For several years alarm has been expressed in the United States,1 and the past 12 months have seen two World Health Organisation meetings prompted by increasing anxieties about the role of antimicrobials in animal husbandry2; a report by Britain’s House of Lords on antimicrobial resistance; and a report from the US Institute of Medicine on emerging infections.3 This week the Danish Chief Medical Officer, Einar Krag, has called together colleagues from the European Union and their advisors for a conference on “the microbial threat” to “assess the strategies to prevent and control the emergence and spread of antimicrobial resistant micro-organisms.” Is all this activity warranted? We believe it is: in the words of the House of Lords’ report, “Resistance to antibiotics ... constitutes a major threat to public health and ought to be recognised as such more widely than it is at present.” This issue of the BMJ is helping to broadcast this message. The causes of these problems and gloomy portents are not difficult to find. In the past 50 years people in both the developed and developing worlds have accepted antibiotics as their right—to obtain a prescription at the first sign of a trivial infection or treat themselves with a handful of cheap antibiotics. We cannot conceive a return to the pre-antibiotic days, yet the unbridled use of these agents in man and animals is inexorably propelling us in that direction. Most antibiotic use is in two areas: in humans in the community, and in animals for growth promotion and prophylaxis (see table). The data in the table suggest that up to 75% of antibiotic use is of questionable therapeutic value.3 What seems less controversial is the long term risk of spraying fruit trees in some parts of the world with antibiotics and adding 50-60 kg of an antimicrobial to each acre of salmon farm.4 Bacteria have evolved very sophisticated means of exchanging DNA, both within their own genus and species and across them. The widespread use of antibiotics will tilt the delicate balance between us and the bacteria. There seems to be an inevitability about this problem. Society demands easy answers to its health problems. The increasing resistance problems of recent years are probably related to the use of increasingly broad spectrum agents (cephalosporins and fluoroquinolones) and crowding of the most vulnerable members of society in day care centres and nursing homes. These problems are compounded by the world wide phenomena of pressure on health care systems for greater efficiency, with higher bed occupancies and stretched nursing and medical care. Added to this are pressures to allow over the counter use of antibiotics in western countries so as to reduce healthcare costs. To effect change much will be required by the medical profession, politicians, the pharmaceutical industry, and not least patients. Without doubt antibiotic prescribing in humans and animals must be prudent, but by how much must antibiotic use be reduced (10-50%?) and to what extent will this affect antibiotic resistance in different bacteria? Will we see a return to more susceptible populations or just keep the current problem in check? Some see the problem as particularly gloomy.3 There are suggestions that as resistant bacteria increase and the available antibiotics decrease transmission from inpatients to the larger population will increase and become a problem to the general public. Certainly, the veterinary profession will be required to change practices, and we commend the House of Lords’ views on the control of valuable agents in animal husbandry. There are some encouraging signs that this may be occurring: at least in developed countries, fish farming is using new techniques such as immunisation instead of antimicrobials. The Swedish experience in reducing the reliance on growth promoters shows that progression can be made without reducing production. Initial problems in the form of increased morbidity and mortality in pig and poultry production were overcome by enhancing the rearing systems.5 There is a need to keep a sharp eye on the development of resistance in animals, but not at the expense of inaction. Secondly, both patients and doctors must reduce their expectations. Antibiotics are commonly prescribed, mainly for the respiratory tract, where the vast majority of infections are caused by viral pathogens. The pressures on both patient and doctor are easily understood: an anxious parent, a sick child, and a doctor faced with diagnostic uncertainty. The solutions are not straightforward. Patients must be educated that most such infections do not require antibiotics—that they may actually be harmful to them and their families (through their effect on beneficial bacteria in the body) and to society at large (through encouraging resistance). All this requires considerable effort and time, not easily achieved in a five minute consultation. The American Academy of Paediatrics has made a start in giving guidance to parents.6 Advances in rapid diagnosis will help to remove uncertainties. The coming years will undoubtedly see the introduction of strict clinical guidelines on antibiotic prescribing. At present there is a tendency to concentrate on which antibiotic to use rather than question whether an antimicrobial is useful at all. More firm guidance is also required on the optimum length of treatment. In many parts of the world simple cystitis is still treated for 5-7 days and the more common chest infections for up to 14 days. The drug regulatory authorities therefore have their part to play in insisting that relevant clinical trials support the licence of an antimicrobial. There is much discussion world wide about surveillance schemes for antimicrobial resistance.7 The major problem is gaining useful denominator data—that is, how to obtain an accurate picture of resistance in a community, be it in hospital or general practice. In hospital it is moderately straightforward, since ward based surveys can be undertaken, but in general practice we have little accurate information. As resistance rates of common pathogens can vary greatly over short distances,8 such surveillance must be undertaken both nationally, so that meaningful broad based policies can be devised, and locally, so that relevant clinical guidelines can be developed. Greater insights are required into how resistance genes spread, especially in the community, where there is a paucity of information. Infection control procedures in child and elderly care units require enhancing. Scientific funding bodies across the European Union should realise that if we are to understand the levers which control antibiotic resistance more fundamental research will require funding. The House of Lords report highlights the problems of funding research in this area of medicine,2 which in the past has mainly come from the pharmaceutical industry. Finally, the pharmaceutical industry, which until recently has been ahead of the resistance race, will also be well advised to increase its commitment to antimicrobial research. Indeed, now that several bacterial genomes have been sequenced, there are signs that this is occurring.9 In this issue, we trust that these and other matters have been confronted. We wish the European Union medical officers’ conference well. The problems they are addressing are real and can be approached only by concerted action as bacteria respect no country’s borders. The past decade has seen the progressive intercontinental spread of methicillin resistant Staphylococcus aureus10 and penicillin resistant Streptococcus pneumoniae,11 and there are concerns about increasing resistance of Salmonella typhi.12 Parochial approaches are therefore doomed to failure.

OBJECTIVES: Pancreatic cancer has a very poor prognosis, largely due to its propensity for early local and distant spread. Histopathologically, most pancreatic cancers are characterized by a prominent stromal/fibrous reaction in and around tumor tissue. The aims of this study were to determine whether (1) the cells responsible for the formation of the stromal reaction in human pancreatic cancers are activated pancreatic stellate cells (PSCs) and (2) an interaction exists between pancreatic cancer cells and PSCs that may facilitate local and distant invasion of tumor. METHODS: Serial sections of human pancreatic cancer tissue were stained for desmin and glial fibrillary acidic protein (stellate cell selective markers) and alpha-smooth muscle actin (alphaSMA), a marker of activated PSC activation, by immunohistochemistry, and for collagen using Sirius Red. Correlation between the extent of positive staining for collagen and alphaSMA was assessed by morphometry. The cellular source of collagen in stromal areas was identified using dual staining methodology, ie, immunostaining for alphaSMA and in situ hybridization for procollagen alpha1I mRNA. The possible interaction between pancreatic cancer cells and PSCs was assessed in vitro by exposing cultured rat PSCs to control medium or conditioned medium from 2 pancreatic cancer cell lines (PANC-1 and MiaPaCa-2) for 24 hours. PSC activation was assessed by cell proliferation and alphaSMA expression. RESULTS: Stromal areas of human pancreatic cancer stained strongly positive for the stellate cell selective markers desmin and GFAP (indicating the presence of PSCs), for alphaSMA (suggesting that the PSCs were in their activated state) and for collagen. Morphometric analysis demonstrated a close correlation (r = 0.77; P < 0.04; 8 paired sections) between the extent of PSC activation and collagen deposition. Procollagen mRNA expression was localized to alphaSMA-positive cells in stromal areas indicating that activated PSCs were the predominant source of collagen in stromal areas. Exposure of PSCs to pancreatic cancer cell secretions in vitro resulted in PSC activation as indicated by significantly increased cell proliferation and alphaSMA expression. CONCLUSIONS: Activated PSCs are present in the stromal reaction in pancreatic cancers and are responsible for the production of stromal collagen. PSC function is influenced by pancreatic cancer cells. Interactions between tumor cells and stromal cells (PSCs) may play an important role in the pathobiology of pancreatic cancer.