Seacroft Hospital

Since 1968 the European Liver Transplant Registry (ELTR) collects prospectively the data of liver transplantation (LT) in 145 centers all over Europe. It represents more than 95% of the overall European data compared to the published official figures [[1]International figures on organ donation and transplantation activities 2009. http://www.transplant-observatory.org.Google Scholar]. This collection is made prospectively through a standardized questionnaire. The first part of the questionnaire includes items regarding date and indication for LT, donor and recipient data, surgical technique of LT, and the immediate postoperative immunosuppression therapy. The second part concerns graft and patient outcome, and immunosuppressive regimen follow-up. Participation in the ELTR is voluntary and a standard computerized database is provided to contributing centers with detailed instructions for the collection of accurate and uniform information [[2]Adam R. McMaster P. O’Grady J.G. Castaing D. Klempnauer J.L. Jamieson N. et al.Evolution of liver transplantation in Europe: report of the European Liver Transplant Registry.Liver Transpl. 2003; 9: 1231-1243Crossref PubMed Scopus (492) Google Scholar]. Along with reports concerning LT for specific hepatic diseases [3Mentha G. Giostra E. Majno P.E. Bechstein W.O. Neuhaus P. O’Grady J. et al.Liver transplantation for Budd-Chiari syndrome: a European study on 248 patients from 51 Centres.J Hepatol. 2006; 44: 520-528Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 4Lerut J. Orlando G. Adam R. Sabbà C. Pfitzmann R. Klempnauer J. et al.Liver transplantation for hereditary hemorrhagic telangiectasia: Report of the European Liver Transplant Registry.Ann Surg. 2006; 244: 854-862Crossref PubMed Scopus (2) Google Scholar, 5Mutimer D.J. Gunson B. Chen J. Berenguer J. Neuhaus P. Castaing D. et al.Impact of donor age and year of transplantation on graft and patient survival following liver transplantation for hepatitis C virus.Transplantation. 2006; 81: 7-14Crossref PubMed Scopus (142) Google Scholar, 6De Kerckhove L. De Meyer M. Verbaandert C. Mourad M. Sokal E. Goffette P. et al.The place of liver transplantation in Caroli’s disease and syndrome.Transpl Int. 2006; 19: 381-388Crossref PubMed Scopus (83) Google Scholar, 7Melzi M.L. Kelly D.A. Colombo C. Jara P. Manzanares J. Colledan M. et al.Liver transplant in cystic fibrosis: a poll among European centers. A study from the European Liver Transplant Registry.Transpl Int. 2006; 19: 726-731Crossref PubMed Scopus (56) Google Scholar, 8Lerut J.P. Orlando G. Adam R. Schiavo M. Klempnauer J. Mirza D. et al.The place of liver transplantation in the treatment of hepatic epitheloid hemangioendothelioma: Report of the European Liver Transplant Registry.Ann Surg. 2007; 246: 949-957Crossref PubMed Scopus (146) Google Scholar, 9Burra P. Senzolo M. Adam R. Delvart V. Karam V. Germani G. et al.Liver transplantation for alcoholic liver disease in Europe: a study from the ELTR (European Liver Transplant Registry).Am J Transplant. 2010; 10: 138-148Crossref PubMed Scopus (254) Google Scholar, 10Schramm C. Bubenheim M. Adam R. Karam V. Buckels J. O‘Grady J.G. et al.Primary liver transplantation for autoimmune hepatitis: a comparative analysis of the European Liver Transplant Registry.Liver Transpl. 2010; 16: 461-469PubMed Google Scholar, 11Mergental H. Porte R.J. Liver transplantation for unresectable hepatocellular carcinoma in patients without liver cirrhosis.Transpl Int. 2010; 23: 662-667Crossref PubMed Scopus (25) Google Scholar, 12Wahlin S. Stål P. Adam R. Karam V. Porte R. Seehofer D. et al.Liver transplantation for erythropoietic protoporphyria in Europe.Liver Transpl. 2011; 17: 1021-1026PubMed Google Scholar], ELTR has allowed the development of risk models for liver-transplantation mortality according to the characteristics of the donor and recipient, and of the transplant procedure [13Adam R. Cailliez V. Majno P. Karam V. McMaster P. Calne Y.C. et al.Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study.Lancet. 2000; 356: 621Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 14Burroughs A.K. Sabin C.A. Rolles K. Delvart V. Karam V. Buckels J. et al.3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome.Lancet. 2006; 367: 225-232Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar]. Quality of the data is assessed routinely. A regular auditing process is conducted each year to ensure the reliability of the scientific analysis of the data, a control of the good adequacy between ELTR questionnaire and patient charts is performed by randomly conducted audit visits. Results of these audit visits have indicated that ELTR data were reliable and the scientific results of ELTR can be considered credible and representative of LT in Europe [15Karam V. Gunson B. Roggen F. Grande L. Wannoff W. Janssen M. et al.Quality control of the European Liver Transplant Registry: Results of audit visits to the contributing Centres.Transplantation. 2003; 75: 2167Crossref PubMed Scopus (48) Google Scholar, 16Morris P. Monaco A. Quality control of transplant registries.Transplantation. 2003; 75: 2162Crossref PubMed Scopus (4) Google Scholar, 17Hanto D. Reliability of voluntary and compulsory databases and registries in the United States.Transplantation. 2003; 75: 2162Crossref PubMed Scopus (20) Google Scholar, 18Van Der Meulen J. Jacob M. Copley L. Assessing the quality of the data in a transplant registry: the European Liver Transplant Registry.Transplantation. 2003; 75: 2164Crossref PubMed Scopus (24) Google Scholar]. In addition, a control quality program has been developed internally. The data are subjected to checks for completeness, consistency, and range. Comprehensive logical intra- and inter-updates are performed. Moreover, the ELTR has established agreements with the European Organ Sharing Organizations (OSO): United Kingdom Transplant Service Support Authority (UKTransplant), Spanish Organizaciòn Nacional de Transplantes (ONT), Scandinavian Scanditransplant (SKT), Dutch Transplant Foundation (NTS), Eurotransplant (ET), French Agence de la Biomédecine (ABM) to exchange data collected from European Centers and to cross check common data between OSO and ELTR. We have first considered all data since 1968 to show the evolution of results of LT in Europe since its initial development. The rest of the analysis has been undertaken during two different periods: (a) from January 1988 to December 2009 (89,865 LT – 80,347 patients), where the date from January 1988 was chosen as corresponding to the diffusion of cyclosporine-based immunosuppression and to the standardization of the surgical procedure, (b) the last 10-year period data from January 2000 to December 2009 (54,088 LT – 48,218 patients) to give a more recent evaluation of LT results in Europe. Data were analyzed as a whole without distinction of pediatric transplants that represent 10% of LTs in Europe. Data are analyzed with Statistical Analysis System (SAS). The dynamics of data control are continued during the statistical analyzes. Calculation of survival rates are determined by the actuarial method. From May 1968 to December 2009, the ELTR collected data concerning 93,634 liver transplantations (LTs) in 83,816 patients from 145 centers of 26 countries (Fig. 1). These data give a comprehensive overview of the status and evolution of LT in Europe. Both the number of transplant centers and the annual number of LTs performed in Europe have gradually increased since the creation of ELTR (Fig. 2). However, after an exponential increase from the eighties, a plateau has become to be reached in recent years with about 5800 LTs performed all over Europe.Fig. 2Evolution of 93,634 LTs performed in Europe since May 1968. Arrows indicate the year the first LT was performed in indicated countries. ∗This decrease is owed to the fact that some centers did not yet send their updating further to the recent changes of the questionnaire.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Main indications for LT in Europe with the corresponding graft and patient survival rates at 1, 5 and 10 years are listed in Table 1. Cirrhosis is the most frequent indication (52%), mainly related to either viral infection (21% with 13% of hepatitis C virus infection (HCV) and 7% of hepatitis B virus infection (HBV)), or alcohol abuse (19%). Combined viral and alcoholic (ALD) cirrhosis represents 3% of cases, with 2% of HCV–ALD. Cirrhosis is followed by three major indications: primary liver tumors (14% with 12.1% of hepatocellular carcinoma), cholestatic disease (11%), and acute hepatic failure (8%, 2% of which are virus-related). Cholestatic disease includes primary biliary cirrhosis (6%) and extra-hepatic biliary atresia (4%). Primary sclerosing cholangitis represents 4% of cases. Biliary atresia is the most frequent indication (57%) in the pediatric population, followed by metabolic disease (19%). Metabolic disease represents 6% of indications with familial amyloïdotic polyneuropathy as the major indication (2%), followed by three indications of equal frequency (1%): Wilson disease, alpha-1-antitrypsin deficiency and hemochromatosis. Secondary tumors (mainly carcinoid), Budd Chiari and benign liver tumors (mainly polycystic disease) represent only 1% of indications in Europe.Table 1Primary indications for LT in Europe and the corresponding survival. Open table in a new tab The percentage of main indications for LT has significantly changed with time. While cancers represented 50% of indications before 1980, they dramatically decreased during the nineties (10%) before resuming a linear increase since 2000, to currently represent more than 20%. Conversely, acute hepatic failure that led anecdotally to LT before 1986 has since become a recognized indication for LT. (Fig. 3). In the 10 recent years, two groups of indication have shown an increase: primary liver tumors (16%), mainly related to HCC, and cirrhosis (53%), mainly alcoholic (20%). Drug-related fulminant hepatitis is henceforth the leading disease in the group of acute hepatic failures. In the same way, primary sclerosing cholangitis is the main indication in the group of cholestatic diseases. Patient and graft survival of this 10-recent-year population are summarized in Table 1. One, 3 and 6-month patient’s survivals were 90%, 85% and 82% before 2000. Survival rates dramatically increased to reach 94%, 91% and 88%, respectively. The critical period for post-LT outcome is the first 6 months: 46% of deaths and 65% of re-LT occurs within 6 months after LT (Fig. 4). In 49% of cases, re-LT is indicated in the month after primary LT, and one quarter of deaths occurs within the first month after LT. Data represented in Table 2, Table 3 correspond to main cause of death or graft failure. Main causes of death in the 18,186 patients (about 23%) who died after primary LT or re-LT were, by decreasing order: (1) general causes as multiple organ failure and cerebrovascular, cardiovascular, pulmonary, and renal complications (29%); (2) recurrence of primary disease (20%), mostly cancer (11%); (3) sepsis (18%) mostly bacterial (9%); (4) technical complications (5%), mostly hemorrhage and vascular (3%); and (5) rejection (4%) mostly chronic (3%) (Table 2). Intra-operative deaths and primary non-function represented 3% of all deaths. When we consider only the patients who survive beyond 6 months (Fig. 5), there are less technical complications, infection and general complications (cerebrovascular, cardiovascular, pulmonary, and renal), but more tumoral and non-tumoral recurrences, de novo tumor and rejection.Table 2Post-LT mortality after first LT in Europe. Complications correspond to first declared cause of death according to date of occurrence. Open table in a new tab Table 3Recipient graft survival according to the type of LT in Europe. Open table in a new tab The data of the last 10 years show a decrease in overall mortality (16%) with the same distribution of the causes of death observed in the population from 1988. When all indications are considered during the entire study period, patient survival rates are 82% at 1 year, 71% at 5 years, 61% at 10 years, 51% at 15 years and 43% at 20 years. When we consider only the patients who survive beyond 6 months, patient survival rates are dramatically higher (96% at 1 year, 83% at 5 years, 71% at 10 years, 61% at 15 years and 52% at 20 years). After an improvement between 1988 and 2000, the survival of these patients appears to be relatively steady since 2000 (Fig. 6). Survival has improved regularly year after year, reaching 85% at 1 year after 2004 compared with 76% in 1990–1994 and only 33% before 1985 (Fig. 7). The improvement concerns all the indications but particularly LT for cancers (Fig. 8).Fig. 8Patient survival according to indication for and year of LT.View Large Image Figure ViewerDownload Hi-res image Download (PPT) When we consider the last 10-year period, survival of patients in the recent 10 years has improved to reach 85% at 1 year and at 5 years. of LTs have been performed in pediatric patients with of than years. survival in is significantly than in adults In the pediatric population, survival is for years and for 3 to 15 years In the 10 last years, the of pediatric LT has decreased to and the corresponding 5 is than in adults The patient survival is significantly for cirrhosis than for primary liver tumors and acute hepatic failure In viral and have a survival than with or The survival rates in metabolic diseases cholestatic disease and biliary disease of the percentage of in these of survival rates at 1, 5 and 15 and 20 years according to the primary indication are listed in Table 1. survival in the last 10-year population was improved in all the most in survival was observed in LTs for primary liver which is liver and acute hepatic failure The of were were than years, were than years. percentage of are from than years in in and in in to the between a and a relatively donor (Fig. survival were from than years was significantly higher than that with from than years at 5 years, 71% at and 50% graft there is to among without risk (Fig. graft survival according to donor Large Image Figure ViewerDownload Hi-res image Download (PPT) When we consider the last 10-year period, graft survival was with than years and with donor than years. However, are more to of than years were in than years, and only were in than years, at in the in survival. In to the survival of pediatric LT an of recipient age is observed for Survival rates are for adults years, for years, and for than years. However, age of has increased during the last and patients than years, who represented less than in the represented of transplant in 2009 (Fig. When we consider the last 10-year period, survival has increased in all the of to reach for adults of years, for years and over years. of LTs were and were were and to In and LTs have survival. In LTs have a survival than LTs LTs have a decreased graft survival as compared to and LTs However, of these in indications 50% survival in patients to a 5 in the last 10-year population was improved in all the groups of type the most in survival was observed in However, only of LTs were than LTs were and of were to LTs have been in recent years before 2000 after In the were represented by (2%), (6%) and transplants 1, 15 and graft survivals of each type of graft are summarized in Table Survival at 5 years was between liver and but than that of and higher than that of and and represented of overall LTs with a graft survival as compared to in indications survival and in indications survival was was less than and of was for When we consider the last 10-year period, graft survival has increased in all of graft to reach for for and for The ELTR has data concerning related LTs performed in centers from 20 countries from to December 2009 (Fig. 1). The results of this technique be published In adults represented 65% of Since pediatric The donor surgical mortality was graft survival of was for than for adults graft survival of was than LT for was for adults graft more technical complications more infection more rejection more tumor recurrence but less general complications and less disease recurrence after than after LT was indicated in mainly for technical complications vascular and biliary for primary non-function and for rejection mainly chronic of primary disease was in only of (Table of re-LT after the first LT in Europe. The complications correspond to the first cause of failure declared according to of occurrence. Open table in a new tab graft survival rates for the second and LTs were and significantly than for primary LT – (Fig. The data of the last 10 years show a decrease in the of re-LT with an increase of technical complications and a decrease of rejection Moreover, graft survival was increased in all the of re-LT and the between primary LT and LT has been more than the ELTR is a to the evolution and results of LT in Europe. It is representative of LT in Europe of LTs to a control of data audit visits to randomly its scientific has been [15Karam V. Gunson B. Roggen F. Grande L. Wannoff W. Janssen M. et al.Quality control of the European Liver Transplant Registry: Results of audit visits to the contributing Centres.Transplantation. 2003; 75: 2167Crossref PubMed Scopus (48) Google Scholar, 16Morris P. Monaco A. Quality control of transplant registries.Transplantation. 2003; 75: 2162Crossref PubMed Scopus (4) Google Scholar, 17Hanto D. Reliability of voluntary and compulsory databases and registries in the United States.Transplantation. 2003; 75: 2162Crossref PubMed Scopus (20) Google Scholar, 18Van Der Meulen J. Jacob M. Copley L. Assessing the quality of the data in a transplant registry: the European Liver Transplant Registry.Transplantation. 2003; 75: 2164Crossref PubMed Scopus (24) Google Scholar]. LTs year are currently performed in a number to that of the United However, donation rates in Europe more than in United for Organ Sharing has by the donation in Europe in followed by most of the European countries with a of organ donation between 20 and to that of in the and which has the donation in figures on donation and European for the Quality of Transplant Scholar]. with a donor that represents the most of LT, to LT as or related LTs are for of all more these give results to that for LT and a number of patients to LT. they from the centers [13Adam R. Cailliez V. Majno P. Karam V. McMaster P. Calne Y.C. et al.Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study.Lancet. 2000; 356: 621Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 14Burroughs A.K. Sabin C.A. Rolles K. Delvart V. Karam V. Buckels J. et al.3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome.Lancet. 2006; 367: 225-232Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar]. This is to the risk for in of has been between the and the of the risk of donor mortality and In of two main from the European (1) as cirrhosis to represent the main indication of LT with more than of the and a within this group of patients with alcoholic and virus C related (2) the major is for mainly HCC, which represents currently of all after a decrease from 50% in the to only 10% in the The of patients within the V. E. R. S. A. F. et al.Liver transplantation for the treatment of hepatocellular in patients with J PubMed Scopus Google with results of survival between and benign hepatic disease this of the most in the evolution of LT is the improvement of results with leading to a survival of all indications This results from a surgical a of patients and an improved post-LT of complications and immunosuppressive therapy. The improvement is particularly for mainly hepatocellular carcinoma as with a of in survival rates from to This was with the data of the last 10 years with an improved survival of and recipient age the quality of the as shown by a analysis of ELTR data on mortality after LT [13Adam R. Cailliez V. Majno P. Karam V. McMaster P. Calne Y.C. et al.Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study.Lancet. 2000; 356: 621Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 14Burroughs A.K. Sabin C.A. Rolles K. Delvart V. Karam V. Buckels J. et al.3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome.Lancet. 2006; 367: 225-232Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar]. However, they are not of the fact that donor age has been as an risk of outcome R. Cailliez V. Majno P. Karam V. McMaster P. Calne Y.C. et al.Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study.Lancet. 2000; 356: 621Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar], the evolution that are to the donor recipient age has been considered as with higher the but LT to improved results and of has not changed with is the critical period of the first 6 months more the first year to the outcome of the than a of the deaths and three of within the first year after LT. that patients have reached the first year after LT, they have an to survive at When 7% of patients), re-LT is with less results than the first LT. However, there is that consider this a to a new LT that a of with the in to of the of the of survival is observed between first and second LT and LTs are not with results than of second of the of recent years has been the development of performed by of the centers. with LT, to more patients with but with to decrease as as for the to be of for mortality and for postoperative However, has to decrease in recent years in Europe the in the where has decreased in liver Full Text Full Text PDF PubMed Scopus Google Scholar]. liver are by accurate information about donor to data is and these from liver donor registries and of donor an for centers with deaths to these to the liver transplantation liver donor where we J 2006; PubMed Scopus Google Scholar, Adam R. J. deaths of hepatic for donor liver Transpl. 2006; PubMed Scopus Google Scholar]. In LT is a of liver disease, acute liver failure and It is relatively as compared to the initial years. are to more of the donor Survival is gradually in to in the surgical procedure and of immunosuppressive therapy. to of liver are to the organ This development the of the evaluation of the in the of countries represent a in the increase the donor to patient death on the and to equal to good indications of LT have become the main of a treatment that of patients to survive at 5 years. The declared that they not have to regarding or of with to this The are to all the 145 contributing centers listed at the following The is by a from and a of the – de ELTR is a of the European Liver and Transplant

Cystic fibrosis (CF) is the most common lethal hereditary disorder with autosomal recessive heredity in caucasians. The majority of CF patients suffer from chronic respiratory infection with the opportunistic bacterial pathogen Pseudomonas aeruginosa. No consensus among clinicians has been reached so far concerning antibiotic treatment against P. aeruginosa in CF patients. Consensus answers to 24 important questions in this context, based on current evidence, are presented, given by a panel of 34 European experts. Questions addressed and answered are: The diagnosis of P. aeruginosa lung colonization in CF; The impact of P. aeruginosa on the clinical state of CF patients; The assessment of P. aeruginosa susceptibility against antibiotics and the importance of these results for the clinician; The use of monotherapy versus combination therapy; The development of microbial resistance; The achievement of optimal airway concentrations; The effects of subinhibitory concentrations of antibiotics on P. aeruginosa; Statements on the pharmacokinetics of antibiotics in CF patients; Recommendations for doses and dosing intervals and length of treatment regimens; and Toxic side effects due to repeated antibiotic therapy was addressed. The expert panel answered further questions on the use of fluoroquinolones in children with CF, on the administration of nebulized antibiotics and whether prevention of P. aeruginosa lung colonization is possible in CF using antibiotic therapy. Problems of antibiotic therapy at home and in the hospital were addressed, a consensus statement on regular maintenance treatment, or treatment on demand, was given and different routes of administration of antibiotics were recommended for different clinical situations. Finally, the factors which determine the choice of the antibiotic, the dosage, and the duration of the treatment in cystic fibrosis patients were addressed and the design of future antibiotic studies in the context of Pseudomonas aeruginosa lung infection in cystic fibrosis patients were recommended.

The European Liver Transplant Registry (ELTR) currently allows for the analysis of 44,286 liver transplantations (LTs) performed on 39,196 patients in a 13-year period. After an exponential increase, the number of LTs is plateauing due to a lack of organs. To cope with this, alternatives to cadaveric LT, such as split LT, domino LT, or living-related LT (LRLT) are being used increasingly. They now account for 11% of all procedures. One of the most important findings in the evolution of LT is the considerable improvement of results along time with, for the mean time, a one-year survival of 83%, all indications confounded. The improvement is particularly significant for cancers. This improvement is mainly represented by hepatocellular carcinoma, with a gain of 17% for 5-year survival rate from 1990 to 2000. Increasingly, older donors are used to augment the donor pool and older recipients are transplanted due to improved results and a better selection of patients. More than two thirds of deaths and three quarters of retransplantations occurred within the first year of transplantation. Retransplantation is associated with much less optimal results than first LT. One of the prominent features of recent years is the development of LRLT. LRLT is now performed by almost half of the European centers. As with split LT or domino LT, LRLT aims to provide more patients to be transplanted. Special attention is paid to reducing the risk for the donor, which is now estimated to be 0.5% mortality and 21% postoperative morbidity.

Whilst many multiparous women are obese (body mass index >30 kg/m(2)), obesity has been associated with impaired fecundity; however, the mechanism which links obesity to reduced fertility remains to be fully elucidated. Obese women, particularly those with central obesity, are less likely to conceive per cycle. Obese women suffer perturbations to the hypothalamic-pituitary-ovarian axis, menstrual cycle disturbance and are up to three times more likely to suffer oligo-/anovulation. A fine hormonal balance regulates follicular development and oocyte maturation, and it has been observed that obesity can alter the hormonal milieu. Leptin, a hormone produced by adipocytes, is elevated in obese women, and raised leptin has been associated with impaired fecundity. Obesity impairs ovulation but has also been observed to detrimentally affect endometrial development and implantation. The expression of polycystic ovary syndrome (PCOS) is regulated, in part, by weight, and so obese women with PCOS often have a more severe phenotype and experience more subfertility. Obesity also impairs the response of women to assisted conception treatments. Weight loss through lifestyle modification or bariatric surgery has been demonstrated to restore menstrual cyclicity and ovulation and improve the likelihood of conception. In this article, we will discuss the effect of obesity upon key reproductive mechanisms and its relation to fertility treatments.

The purpose of this registry study was to provide an overview of trends and results of liver transplantation (LT) in Europe from 1968 to 2016. These data on LT were collected prospectively from 169 centers from 32 countries, in the European Liver Transplant Registry (ELTR) beginning in 1968. This overview provides epidemiological data, as well as information on evolution of techniques, and outcomes in LT in Europe over more than five decades; something that cannot be obtained from only a single center experience.

Background
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\nPolycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia occurs secondary to insulin resistance and is associated with increased risk of cardiovascular disease and diabetes mellitus. Insulin‐sensitising agents such as metformin may be effective in treating PCOS‐related anovulation.
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\nObjectives
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\nTo evaluate the effectiveness and safety of insulin‐sensitising drugs in improving reproductive and metabolic outcomes for women with PCOS undergoing ovulation induction.
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\nSearch methods
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\nWe searched the following databases from inception to January 2017: Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. We searched registers of ongoing trials and reference lists from relevant studies.
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\nSelection criteria
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\nWe included randomised controlled trials of insulin‐sensitising drugs compared with placebo, no treatment, or an ovulation‐induction agent for women with oligo and anovulatory PCOS.
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\nData collection and analysis
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\nTwo review authors independently assessed studies for eligibility and bias. Primary outcomes were live birth rate and gastrointestinal adverse effects. Secondary outcomes included other pregnancy outcomes, menstrual frequency and metabolic effects. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I2 statistic and reported quality of the evidence for primary outcomes using GRADE methodology.
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\nMain results
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\nWe assessed the interventions metformin, clomiphene citrate, metformin plus clomiphene citrate, D‐chiro‐inositol, rosiglitazone and pioglitazone. We compared these with each other, placebo or no treatment. We included 48 studies (4451 women), 42 of which investigated metformin (4024 women). Evidence quality ranged from very low to moderate. Limitations were risk of bias (poor reporting of methodology and incomplete outcome data), imprecision and inconsistency.
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\nMetformin versus placebo or no treatment
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\nThe evidence suggests that metformin may improve live birth rates compared with placebo (OR 1.59, 95% CI 1.00 to 2.51, 4 studies, 435 women, I2 = 0%, low‐quality evidence). The metformin group experienced more gastrointestinal side effects (OR 4.76, 95% CI 3.06 to 7.41, 7 studies, 670 women, I2 = 61%, moderate‐quality evidence) but had higher rates of clinical pregnancy (OR 1.93, 95% CI 1.42 to 2.64, 9 studies, 1027 women, I2 = 43%, moderate‐quality evidence), ovulation (OR 2.55, 95% CI 1.81 to 3.59, 14 studies, 701 women, I2 = 58%, moderate‐quality evidence) and menstrual frequency (OR 1.72, 95% CI 1.14 to 2.61, 7 studies, 427 women, I2 = 54%, low‐quality evidence). There was no clear evidence of a difference in miscarriage rates (OR 1.08, 95% CI 0.50 to 2.35, 4 studies, 748 women, I2 = 0%, low‐quality evidence).
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\nMetformin plus clomiphene citrate versus clomiphene citrate alone
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\nThere was no conclusive evidence of a difference between the groups in live birth rates (OR 1.21, 95% CI 0.92 to 1.59, 9 studies, 1079 women, I2 = 20%, low‐quality evidence), but gastrointestinal side effects were more common with combined therapy (OR 3.97, 95% CI 2.59 to 6.08, 3 studies, 591 women, I2 = 47%, moderate‐quality evidence). However, the combined therapy group had higher rates of clinical pregnancy (OR 1.59, 95% CI 1.27 to 1.99, 16 studies, 1529 women, I2 = 33%, moderate‐quality evidence) and ovulation (OR 1.57, 95% CI 1.28 to 1.92, 21 studies, 1624 women, I2 = 64%, moderate‐quality evidence). There was a statistically significant difference in miscarriage rate per woman, with higher rates in the combined therapy group (OR 1.59, 95% CI 1.03 to 2.46, 9 studies, 1096 women, I2 = 0%, low‐quality evidence) but this is of uncertain clinical significance due to low‐quality evidence, and no clear difference between groups when we analysed miscarriage per pregnancy (OR 1.30, 95% CI 0.80 to 2.12, 8 studies; 400 pregnancies, I2 = 0%, low‐quality evidence).
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\nMetformin versus clomiphene citrate
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\nWhen all studies were combined, findings for live birth were inconclusive and inconsistent (OR 0.71, 95% CI 0.49 to 1.01, 5 studies, 741 women, I2 = 86%, very low‐quality evidence). In subgroup analysis by obesity status, obese women had a lower birth rate in the metformin group (OR 0.30, 95% CI 0.17 to 0.52, 2 studies, 500 women, I2 = 0%, very low‐quality evidence), while data from the non‐obese group showed a possible benefit from metformin, with high heterogeneity (OR 1.71, 95% CI 1.00 to 2.94, 3 studies, 241 women, I2 = 78%, very low‐quality evidence). Similarly, among obese women taking metformin there were lower rates of clinical pregnancy (OR 0.34, 95% CI 0.21 to 0.55, 2 studies, 500 women, I2 = 0%, very low‐quality evidence) and ovulation (OR 0.29, 95% CI 0.20 to 0.43 2 studies, 500 women, I2 = 0%, low‐quality evidence) while among non‐obese women, the metformin group had more pregnancies (OR 1.56, 95% CI 1.05 to 2.33, 5 studies, 490 women, I2 = 41%, very low‐quality evidence) and no clear difference in ovulation rates (OR 0.81, 95% CI 0.51 to 1.28, 4 studies, 312 women, low‐quality evidence, I2=0%). There was no clear evidence of a difference in miscarriage rates (overall: OR 0.92, 95% CI 0.50 to 1.67, 5 studies, 741 women, I2 = 52%, very low‐quality evidence).
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\nD‐chiro‐inositol (2 studies), rosiglitazone (1 study) or pioglitazone (1 study) versus placebo or no treatment
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\nWe were unable to draw conclusions regarding other insulin‐sensitising drugs as no studies reported primary outcomes.

National guidance and clinical guidelines recommended multidisciplinary teams (MDTs) for cancer services in order to bring specialists in relevant disciplines together, ensure clinical decisions are fully informed, and to coordinate care effectively. However, the effectiveness of cancer teams was not previously evaluated systematically. A random sample of 72 breast cancer teams in England was studied (548 members in six core disciplines), stratified by region and caseload. Information about team constitution, processes, effectiveness, clinical performance, and members' mental well-being was gathered using appropriate instruments. Two input variables, team workload (P=0.009) and the proportion of breast care nurses (P=0.003), positively predicted overall clinical performance in multivariate analysis using a two-stage regression model. There were significant correlations between individual team inputs, team composition variables, and clinical performance. Some disciplines consistently perceived their team's effectiveness differently from the mean. Teams with shared leadership of their clinical decision-making were most effective. The mental well-being of team members appeared significantly better than in previous studies of cancer clinicians, the NHS, and the general population. This study established that team composition, working methods, and workloads are related to measures of effectiveness, including the quality of clinical care.

BACKGROUND: Patients with cystic fibrosis (CF) have many risk factors for reduced bone mineral density (BMD). The aim of this study was to determine the prevalence of osteoporosis and osteopenia in a large cross section of patients and to identify risk factors. METHODS: All patients attending the regional centre were invited to participate in the study. Bone mineral density was measured at the lumbar spine, femoral neck, and for total body with a Lunar DPX-L densitometer. Multiple indices of disease severity were investigated, and liver and thyroid function, blood calcium, phosphate, 25-OH vitamin D, follicle stimulating and luteinising hormone, oestradiol, and testosterone levels were measured. Patients completed a four day prospective dietary diary. Exercise was assessed by a seven day activity recall questionnaire. Sexual development and treatment histories were obtained. The relationship between all these variables and BMD measurements was analysed. RESULTS: Sixty six percent of 114 patients assessed had osteopenia or osteoporosis. The Shwachman-Kulczycki (SK) clinical score (higher score = less severe disease) correlated significantly with BMD at the lumbar spine and femoral neck, and with total body BMD (p<0.001). There was a predicted increase of 0.0032 g/cm(2) in lumbar spine BMD for every unit increase in the SK score. Oral steroid use was significantly associated with reduced BMD at the lumbar spine (p = 0.017) and femoral neck (p = 0.027). CONCLUSIONS: Osteopenia and osteoporosis are common findings in a heterogeneous population of adults with CF. Patients at most risk are those with severe disease and those who have used corticosteroids.

BACKGROUND: Cancer-related pain is complex and multi-dimensional but the mainstay of cancer pain management has predominantly used a biomedical approach. There is a need for non-pharmacological and innovative approaches. Transcutaneous Electric Nerve Stimulation (TENS) may have a role in pain management but the effectiveness of TENS is currently unknown. This is an update of the original review published in Issue 3, 2008. OBJECTIVES: The aim of this systematic review was to determine the effectiveness of TENS for cancer-related pain in adults. SEARCH METHODS: The initial review searched The Cochrane Library, MEDLINE, EMBASE, CINAHL, PsychINFO, AMED and PEDRO databases in April 2008. We performed an updated search of CENTRAL, MEDLINE, EMBASE, CINAHL and PEDRO databases in November 2011. SELECTION CRITERIA: We included only randomised controlled trials (RCTS) investigating the use of TENS for the management of cancer-related pain in adults. DATA COLLECTION AND ANALYSIS: The search strategy identified a further two studies for possible inclusion. One of the review authors screened each abstract using a study eligibility tool. Where eligibility could not be determined, a second author assessed the full paper. One author used a standardised data extraction sheet to collect information on the studies and independently assess the quality of the studies using the validated five-point Oxford Quality Scale. The small sample sizes and differences in patient study populations of the three included studies (two from the original review and a third included in this update) prevented meta-analysis. For the original review the search strategy identified 37 possible published studies; we divided these between two pairs of review authors who decided on study selection; all four review authors discussed and agreed final scores. MAIN RESULTS: Only one additional RCT met the eligibility criteria (24 participants) for this updated review. Although this was a feasibility study, not designed to investigate intervention effect, it suggested that TENS may improve bone pain on movement in a cancer population. The initial review identified two RCTs (64 participants) therefore this review now includes a total of three RCTs (88 participants). These studies were heterogenous with respect to study population, sample size, study design, methodological quality, mode of TENS, treatment duration, method of administration and outcome measures used. In one RCT, there were no significant differences between TENS and placebo in women with chronic pain secondary to breast cancer treatment. In the other RCT, there were no significant differences between acupuncture-type TENS and sham in palliative care patients; this study was underpowered. AUTHORS' CONCLUSIONS: Despite the one additional RCT, the results of this updated systematic review remain inconclusive due to a lack of suitable RCTs. Large multi-centre RCTs are required to assess the value of TENS in the management of cancer-related pain in adults.

BACKGROUND: Patients with chronic disease comply with about 50% of their treatment. The complex and time consuming daily drug regimens needed in the care of adult patients with cystic fibrosis encourage non-compliance with prescribed treatments. Understanding the reasons for, and the extent of, non-compliance is essential for a realistic appraisal of the patient's condition and sensible planning of future treatment programmes. METHODS: Patients were invited to complete a questionnaire which asked about their compliance with daily treatment. The data were used to calculate a compliance score, the percentage of prescribed treatment taken, and to examine patient attitudes to each individual prescription. An assessment score derived from consultant, cystic fibrosis research fellow, specialist nurse, and physiotherapist ratings of patient compliance was compared with the compliance score. Both scores were correlated with patient characteristics and disease severity, and the compliance score was also correlated with the patient's knowledge of cystic fibrosis. RESULTS: More than half the patients claimed to take more than 80% of their treatments. Compliance with individual treatments varied according to their perceived unpleasantness and degree of infringement on daily activities. The most common reason given for omitting treatment was forgetfulness. Professional carers were poor judges of patient compliance. There was no correlation between compliance and patients' sociodemographic characteristics or their knowledge about cystic fibrosis. CONCLUSIONS: Non-compliance is universal and should be recognised as normal behaviour. There are no reliable criteria for predicting any patient's level of compliance. Treatment protocols should be planned around individual patient's requirements, modifying treatment ideals where necessary according to the exigency and pattern of that patient's lifestyle.

Rheumatoid arthritis (RA) is a chronic, inflammatory disease of the synovium of uncertain pathogenesis. A number of phenotypic and functional T-cell defects have been described in RA, including abnormal clonal expansions and suppressed proliferative responses, which suggest a defect in T-cell differentiation. Here, we show that RA patients possess fewer naive CD4(+) T cells than healthy controls. Furthermore, a smaller proportion of these cells contains a T-cell receptor excision circle (TREC). Patients with RA also have unusual populations of T cells. These include immature cells characterized as CD45RB(bright)CD45RA(+)CD62L(-) by flow cytometry and a large population that coexpresses CD45RA and CD45RO. These cells are hyperresponsive to mitogen and TCR stimulation when compared to naive cells. Additionally, an unusual putative central memory subset expressing CD62L, but not CD45RA, appears in RA patients at the expense of more typical cells. Levels of C-reactive protein correlate inversely with the TREC content of naive T cells and positively with the sizes of naive and immature atypical T-cell subsets. These data suggest that inflammation drives proliferation of naive T cells in RA and encourages their differentiation into atypical, hyperresponsive progeny. TREC content of individual naive and atypical T-cell subsets suggests an ontogeny consistent with this hypothesis. These studies provide further evidence of a T-cell differentiation defect in RA, which could explain some of the well-characterized immunologic features of the disease.

DNA was extracted from faecal samples collected from 1680 patients in which Cryptosporidium oocysts were recognised by light microscopy. DNA from faeces from five of these patients failed to amplify by PCR three gene fragments--the Cryptosporidium oocyst wall protein (COWP) gene, the thrombospondin-related adhesive protein of Cryptosporidium-1 (TRAP-C1) gene and the thrombospondin-related adhesive protein of Cryptosporidium-2 (TRAP-C2) gene--with primers designed from C. parvum sequences. However, DNA from these five patients did amplify cryptosporidial 18S rDNA gene fragments and a heat-shock protein (HSP70) gene fragment was also amplified from four of them. The purpose of this study was to characterise further the Cryptosporidium associated with infection in these patients. DNA sequence analysis of 18S rDNA genes showed that four of these patients were infected by C. felis, and the remaining one by an as yet un-named Cryptosporidium species designated the 'dog type' (C. dt). Infection by C. felis was further confirmed in all four patients by DNA sequence analysis of the HSP70 gene. Oocysts present in all five samples reacted strongly with two anti-cryptosporidial oocyst monoclonal antibodies, except for the C. dt, which was tested with only one of the antibodies. Two of the patients infected by C. felis had underlying illness; one 8-year-old male had an undefined severe inherited underlying condition, and the second patient, a 32-year-old male, was HIV positive. Two of the remaining three patients (two females aged 1 and 2 years, respectively) were apparently immunocompetent (one infected with C. felis and one with the C. dt). No information was obtained for the fifth patient. The patient infected by C. dt had a recent history of travel to Africa. This is the first report of infection with these two Cryptosporidium species in immunocompetent patients, and in any patient in the UK.

BACKGROUND: Disruption of ovulation occurs in different types of clinical infertility. The World Health Organization (WHO) has provided a classification of ovulation disorders. This review focuses on WHO group 2 anovulation. METHODS: Searches were performed in Medline/PubMed and EMBASE. Each subject summary was presented to the European Society of Human Reproduction and Embryology (ESHRE) Workshop Group, where omissions or disagreements were resolved by discussion. RESULTS: Disorders resulting in ovulatory disturbances are a relatively common cause of infertility. They occur most frequently in the context of WHO group 2 anovulation as reflected, for example, in the polycystic ovary syndrome (PCOS). The aetiology of PCOS remains unclear but evidence exists for a multifactorial origin with a genetic predisposition. Women with PCOS show an increased time to pregnancy but their eventual family size is not necessarily reduced. Also their frequency of miscarriage does not appear increased. Clomiphene citrate is still the first-line treatment in subfertile anovulatory patients with PCOS, with gonadotrophins and laparoscopic ovarian surgery as second-line options. Aromatase inhibitors show promising results. CONCLUSIONS: Long-term health risks in patients with WHO group 2 anovulation demand their general health be monitored, even after their reproductive needs have been fulfilled. Metabolic and cardiovascular risk prevention in women with PCOS should start as early as possible. It is not easy to analyse the possible role of PCOS, independent of obesity, metabolic syndrome, insulin resistance and diabetes, on long-term health.

We have examined the factors influencing prognosis in over 4000 children with acute lymphoblastic leukaemia (ALL) aged 1-14 who have been treated on consecutive MRC UKALL trials from 1972 to 1990. During this time the results of treatment have improved steadily but are consistently superior in girls when compared with boys; the 5-year event-free survival in girls improving from 51% to 71% and in boys from 31% to 57%. These results were independent of age and presenting leucocyte count. Boys not only had a testicular relapse rate of 10% but an excess of bone marrow relapse, particularly evident after 2 years from diagnosis. Other prognostic factors included organomegaly and the morphology of leukaemic blast cells; immunophenotype of the leukaemia, however, had no independent significance after allowance for age, sex and leucocyte count. The influence of sex on prognosis was reaffirmed when we examined various methods of identifying children at highest risk of treatment failure for whom alternative therapy such as bone marrow transplantation might be justified. In MRC UKALL X children had been deemed 'high risk' on the basis of leucocyte count alone, but with further follow-up it has become apparent that girls with an initial leucocyte count of > 100 x 10(9)/l have a similar prognosis to boys with a lower count. We therefore derived a risk score based on sex, age and count which has given better discrimination between standard risk (66% 5-year survival) and poor risk (39%) survival than other methods. This group of worse-risk children includes 16% of boys but only 3% of all girls. Gender remains an important prognostic factor in UKALL trials and there are very few girls who are at highest risk of treatment failure. The reasons for this remain unclear, but the pattern of relapses suggests that boys more often get inadequate systemic therapy. We postulate that the reasons for treatment failure may relate to sensitivity to continuing (maintenance) chemotherapy.

BACKGROUND: Patients with cystic fibrosis have received more intravenous antibiotic courses as median survival has steadily increased. A number of centres have adopted a policy of regular (three monthly) rather than on demand intravenous antipseudomonal antibiotics. More widespread bacterial antibiotic resistance has resulted from this increased antibiotic use. Most Pseudomonas aeruginosa strains remain fully sensitive to colistin but its use has been resisted owing to concerns about neurotoxicity and nephrotoxicity. A study was carried out to assess the safety and efficacy of intravenous colistin in the treatment of acute respiratory exacerbations in adult patients with cystic fibrosis. METHODS: Patients with chronic Pseudomonas aeruginosa colonisation who presented with protocol defined respiratory tract exacerbations were randomised to receive treatment for 12 days with either colistin (2 MU tds intravenously) alone or with a second anti-pseudomonal antibiotic. Comparisons of the absolute values of respiratory function tests on days 1, 5, and 12 and of overnight oxygen saturation on days 1 and 12 were the primary outcome measures. Patient's weight, clinical and chest radiographic scores, and peripheral blood markers of inflammation were also documented. The effect of each treatment regimen individually was assessed by the change in clinical measurements from baseline values. Adverse renal effects were monitored by measurement of serum levels of urea and electrolytes, creatinine clearance, and ward urine testing. Neurotoxicity was monitored by direct questioning for symptoms. RESULTS: Fifty three patients, 18 of whom entered the study twice, were enrolled. The mean forced expiratory volume in one second (FEV1) increased significantly in both groups, mean forced vital capacity (FVC) only with dual therapy. Both groups showed a non-significant increase in overnight oxygen saturation. All patients showed clinical improvement. Thirty seven adverse neurological events (two severe) were reported in 33 patients in the monotherapy group and 37 (none severe) in 36 patients in the dual therapy group. One patient withdrew because of severe weakness and dizziness. All other adverse neurological events were well tolerated and resolved during or shortly after treatment. Significant changes were seen in mean serum urea levels in both groups, but in only four patients to a level above the normal range, and in creatinine clearance in the dual therapy group. At 24 month follow up no long term adverse consequences from intravenous colistin were found in patients who completed the study. CONCLUSIONS: Intravenous colistin is an effective treatment for Pseudomonas aeruginosa associated pulmonary exacerbations in patients with cystic fibrosis. Assessment of the individual effect of each treatment regimen suggests a greater efficacy when colistin is combined with a second antibiotic to which the pseudomonas shows in vitro sensitivity. Changes in renal function should be monitored.

BACKGROUND: Sperm selection strategies aimed at improving success rates of intracytoplasmic sperm injection (ICSI) include binding to hyaluronic acid (herein termed hyaluronan). Hyaluronan-selected sperm have reduced levels of DNA damage and aneuploidy. Use of hyaluronan-based sperm selection for ICSI (so-called physiological ICSI [PICSI]) is reported to reduce the proportion of pregnancies that end in miscarriage. However, the effect of PICSI on livebirth rates is uncertain. We aimed to investigate the efficacy of PICSI versus standard ICSI for improving livebirth rates among couples undergoing fertility treatment. METHODS: and a follicle-stimulating hormone (FSH) concentration of 3·0-20·0 mIU/mL or, if no FSH measurement was available, an anti-müllerian hormone concentration of at least 1·5 pmol/L. Eligible men (aged 18-55 years) had not had a vasovasostomy or been treated for cancer in the 24 months before recruitment and were able, after at least 3 days of sexual abstinence, to produce freshly ejaculated sperm for the treatment cycle. Couples were randomly assigned (1:1) with an online system to receive either PICSI or a standard ICSI procedure. The primary outcome was full-term (≥37 weeks' gestational age) livebirth, which was assessed in all eligible couples who completed follow-up. This trial is registered, number ISRCTN99214271. FINDINGS: Between Feb 1, 2014, and Aug 31, 2016, 2772 couples were randomly assigned to receive PICSI (n=1387) or ICSI (n=1385), of whom 2752 (1381 in the PICSI group and 1371 in the ICSI group) were included in the primary analysis. The term livebirth rate did not differ significantly between PICSI (27·4% [379/1381]) and ICSI (25·2% [346/1371]) groups (odds ratio 1·12, 95% CI 0·95-1·34; p=0·18). There were 56 serious adverse events in total, including 31 in the PICSI group and 25 in the ICSI group; most were congenital abnormalities and none were attributed to treatment. INTERPRETATION: Compared with ICSI, PICSI does not significantly improve term livebirth rates. The wider use of PICSI, therefore, is not recommended at present. FUNDING: National Institute for Health Research Efficacy and Mechanism Evaluation Programme.

BACKGROUND: Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia occurs secondary to insulin resistance and is associated with an increased biochemical risk profile for cardiovascular disease and an increased prevalence of diabetes mellitus. Insulin-sensitising agents such as metformin may be effective in treating PCOS-related anovulation. This is an update of Morley 2017 and only includes studies on metformin. OBJECTIVES: To evaluate the effectiveness and safety of metformin in combination with or in comparison to clomiphene citrate (CC), letrozole and laparoscopic ovarian drilling (LOD) in improving reproductive outcomes and associated gastrointestinal side effects for women with PCOS undergoing ovulation induction. SEARCH METHODS: We searched the following databases from inception to December 2018: Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. We searched registers of ongoing trials and reference lists from relevant studies. SELECTION CRITERIA: We included randomised controlled trials of metformin compared with placebo, no treatment, or in combination with or compared with CC, letrozole and LOD for women with PCOS subfertility. DATA COLLECTION AND ANALYSIS: statistic and reported quality of the evidence for primary outcomes and reproductive outcomes using GRADE methodology. MAIN RESULTS: = 36%; 6 studies, 781 women; low-quality evidence) and no studies reported gastrointestinal side effects. AUTHORS' CONCLUSIONS: Our updated review suggests that metformin may be beneficial over placebo for live birth however, more women probably experience gastrointestinal side effects. We are uncertain if metformin plus CC improves live birth rates compared to CC alone, but gastrointestinal side effects are probably increased with combined therapy. When metformin was compared with CC, data for live birth were inconclusive, and the findings were limited by lack of evidence. Results differed by body mass index (BMI), emphasising the importance of stratifying results by BMI. No studies reported gastrointestinal side effects in this comparison. Due to the low quality of the evidence, we are uncertain of the effect of metformin on miscarriage in all three comparisons.

OBJECTIVE: To investigate whether a reminder chart improved patients' compliance with their drug regimen after discharge from hospital. DESIGN: Patients were randomly allocated to one of four groups. Two groups received the reminder chart: one also received routine counselling from a nurse and the other received structured counselling from a pharmacist, which included an explanation of the reminder chart. The other two groups received only counseling, either from a nurse or from a pharmacist. Patients were visited about 10 days later: they were questioned about their drug regimen, and their compliance was measured by tablet counting. SETTING: The pharmacy in a district general hospital and patients' homes. PATIENTS: 197 patients being discharged from hospital who were regularly taking two or more drugs. INTERVENTION: An individualised reminder chart, which listed each person's medicines and when they were to be taken and was automatically generated by a medicine labelling computer. MAIN OUTCOME MEASURES: Patient's compliance with and knowledge of their drug regimen. MAIN RESULTS: Of the patients who received the reminder chart, 83% (95% confidence interval 74% to 90%) correctly described their dose regimen compared with 47% (37% to 58%) of those without the chart (p < 0.001). The mean compliance score was 86% (81% to 91%) in both groups not given the reminder chart; 91% (87% to 94%) in the group given the chart without an explanation; and 95% (93% to 98%) in the group given the chart and an explanation. A mean compliance score of > 85% was achieved by 63% (53% to 73%) of patients without a reminder chart and by 86% (78% to 93%) of those receiving the chart (p < 0.001). CONCLUSIONS: An automatically generated reminder chart is a practical and cost effective aid to compliance.

This study investigated the relationship between human preimplantation embryo metabolism and aneuploidy rates during development in vitro. One hundred and eighty-eight fresh and cryopreserved embryos from 59 patients (33.9 +/- 0.6 years) were cultured for 2-5 days. The turnover of 18 amino acids was measured in spent media by high-performance liquid chromatography. Embryos were either fixed for interphase fluorescent in situ hybridization analysis of chromosomes 13, 18, 19, 21, X or Y, or were assayed for mitochondrial activity. Amino acid turnover was different (P < 0.05) between stage-matched fresh and cryopreserved embryos due to blastomere loss following warming. The proportion of embryos with aneuploid cells increased as cell division progressed from pronucleate- (23%) to late cleavage stages (50-70%). Asparagine, glycine and valine turnover was significantly different between uniformly genetically normal and uniformly abnormal embryos on Days 2-3 of culture. By Days 3-4, the profiles of serine, leucine and lysine differed between uniformly euploid versus aneuploid embryos. Gender significantly (P < 0.05) affected the metabolism of tryptophan, leucine and asparagine by cleavage-stage embryos. Pronucleate zygotes had a significantly higher proportion of active:inactive mitochondria compared with cleavage-stage embryos. Furthermore, mitochondrial activity was correlated (P < 0.05) with altered aspartate and glutamine turnover. These results demonstrate the association between the metabolism, cytogenetic composition and health of human embryos in vitro.

BACKGROUND: Since the 1970s, when endogenous opioids and opioid receptors were first isolated in the central nervous system, attempts have been made to optimize opioid therapy by delivering the medication centrally rather than systemically. Although the vast majority of cancer patients obtain satisfactory pain relief from individualized systemic treatment, there remain the few whose pain is refractory to systemic treatments. These patients may obtain relief from neuraxial opioid therapy: intracerebroventricular, epidural or subarachnoid. OBJECTIVES: To compare intracerebroventricular therapy with other neuraxial treatments and to determine whether intracerebroventricular (ICV) has anything to offer over epidural (EPI) and subarachnoid (SA) catheters in terms of efficacy, adverse effects, and complications. SEARCH STRATEGY: A number of electronic databases were searched to retrieve information for inclusion in this review. Non-English language reports are awaiting assessment. Unpublished data were not sought. SELECTION CRITERIA: Randomised studies of intracerebroventricular therapy for patients with intractable cancer pain were sought. However, this level of evidence was not available so data from uncontrolled trials, retrospective case series and uncontrolled prospective cohort studies were assessed. DATA COLLECTION AND ANALYSIS: Our search did not retrieve any controlled trials. We therefore used data from uncontrolled studies to compare incidences of analgesic efficacy, adverse effects, and complications. We found 72 uncontrolled trials assessing ICV (13 trials, 337 patients), EPI (31 trials, 1343 patients), and SA (28 trials, 722 patients) in cancer patients. From these we extracted data on analgesic efficacy, common pharmacologic adverse effects, and complications. MAIN RESULTS: Data from uncontrolled studies reported excellent pain relief among 73% of ICV patients compared with 72% EPI and 62% SA. Unsatisfactory pain relief was low in all treatment groups. Persistent nausea, persistent and transient urinary retention, transient pruritus, and constipation occurred more frequently with EPI and SA. Respiratory depression, sedation and confusion were most common with ICV. The incidence of major infection when pumps were used with EPI and SA was zero. There was a lower incidence of other complications with ICV therapy than with EPI or SA. AUTHORS' CONCLUSIONS: Neuraxial opioid therapy is often effective for treating cancer pain that has not been adequately controlled by systemic treatment. However, long-term use of neuraxial therapy can be complicated by problems associated with the catheters. The data from uncontrolled studies suggests that ICV is at least as effective against pain as other neuraxial treatments and may be a successful treatment for patients whose cancer pain is resistant to other treatments.