Combination of gefitinib and methotrexate to treat tubal ectopic pregnancy (GEM3): a multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND: Tubal ectopic pregnancies can cause substantial morbidity or even death. Current treatment is with methotrexate or surgery. Methotrexate treatment fails in approximately 30% of women who subsequently require rescue surgery. Gefitinib, an epidermal growth factor receptor inhibitor, might improve the effects of methotrexate. We assessed the efficacy of oral gefitinib with methotrexate, versus methotrexate alone, to treat tubal ectopic pregnancy. METHODS: We performed a multicentre, randomised, double-blind, placebo-controlled trial across 50 UK hospitals. Participants diagnosed with tubal ectopic pregnancy were administered a single dose of intramuscular methotrexate (50 mg/m2) and randomised (1:1 ratio) to 7 days of additional oral gefitinib (250 mg daily) or placebo. The primary outcome, analysed by intention to treat, was surgical intervention to resolve the ectopic pregnancy. Secondary outcomes included time to resolution of ectopic pregnancy and serious adverse events. This trial is registered at the ISRCTN registry, ISCRTN 67795930. FINDINGS: Between Nov 2, 2016, and Oct 6, 2021, 328 participants were allocated to methotrexate and gefitinib (n=165) or methotrexate and placebo (n=163). Three participants in the placebo group withdrew. Surgical intervention occurred in 50 (30%) of 165 participants in the gefitinib group and in 47 (29%) of 160 participants in the placebo group (adjusted risk ratio 1·15, 95% CI 0·85 to 1·58; adjusted risk difference -0·01, 95% CI -0·10 to 0·09; p=0·37). Without surgical intervention, median time to resolution was 28·0 days in the gefitinib group and 28·0 days in the placebo group (subdistribution hazard ratio 1·03, 95% CI 0·75 to 1·40). Serious adverse events occurred in five (3%) of 165 participants in the gefitinib group and in six (4%) of 162 participants in the placebo group. Diarrhoea and rash were more common in the gefitinib group. INTERPRETATION: In women with a tubal ectopic pregnancy, adding oral gefitinib to parenteral methotrexate does not offer clinical benefit over methotrexate and increases minor adverse reactions. FUNDING: National Institute of Health Research

Health disparities by occupation, modified by education: a cross-sectional population study

<p>Abstract</p> <p>Background</p> <p>Socio-economic disparities in health status are frequently reported in research. By comparison with education and income, occupational status has been less extensively studied in relation to health status or the occurrence of specific chronic diseases. The aim of this study was to investigate health disparities in the working population based on occupational position and how they were modified by education.</p> <p>Methods</p> <p>Our data were derived from the National Survey of General Practice that comprised 104 practices in the Netherlands. 136,189 working people aged 25–64 participated in the study. Occupational position was assessed by the International Socio-Economic Index of occupational position (ISEI). Health outcomes were self-perceived health status and physician-diagnosed diseases. Odds ratios were estimated using multivariate logistic regression analysis.</p> <p>Results</p> <p>The lowest occupational position was observed to be associated with poor health in men (OR = 1.6, 95% CI 1,5 to 1.7) and women (OR = 1.3, 95% CI 1.2 to 1.4). The risk of poor health gradually decreased in relation to higher occupational positions. People with the lowest occupational positions were more likely to suffer from depression, diabetes, ischaemic heart disease, arthritis, muscle pain, neck and back pain and tension headache, in comparison to people with the highest occupational position (OR 1.2 to 1.6). A lower educational level induced an additional risk of poor health and disease. We found that gender modified the effects on poor health when both occupational position and education were combined in the analysis.</p> <p>Conclusion</p> <p>A low occupational position was consistently associated working people with poor health and physician-diagnosed morbidity. However a low educational level was not. Occupational position and education had a combined effect on self-perceived health, which supports the recent call to improve the conceptual framework of health disparities.</p

Effectiveness of different methods of health education: A comparative assessment in a scientific conference

ABSTRACT: BACKGROUND: Every individual mode of health education has its own merits, drawbacks as well as their own sphere of effectiveness. A specific mode of communication is more useful in a specific setting on a specific group than others. To search for optimum mode of communication for a specific audience is a major area of research in health education. The issue of imparting health education to a gathering of educated people, representing different fields of knowledge has remained a relatively less lighted aspect of health education research. In this backdrop this study was initiated for making a comparative assessment of different methods of dissemination of health education among educated people. METHODS: A cross-sectional interviewer administered questionnaire survey was conducted involving 142 randomly selected subjects during the last session of a five-day conference having health as main theme when the opinion of the delegates regarding different communication methods was asked for. Collected data was analyzed not only to find out the optimum mode of education dissemination in such a setting but also to find the contribution of different factors in the preferences of the study subjects. RESULTS: The participants opted more (60%) for focused programs of smaller audience (sectional program). In both broad area (main program) and focused area programs (sectional), the participants preferred lectures (62% and 65.7% respectively). Specific topics were preferred both in lectures (67.6%) and symposia (57.7%). In the exhibition, exhibits seemed to be more attractive (62%) than the posters. Qualification has emerged to be a contributing factor in peoples' choice towards sectional programme and also in their affinity to symposia. Increased age was a significant contributor in participants' preference towards specific topics. Physical barriers of communication appeared to be a problem in the main program as well as in the exhibition. Lack of coherence among the speakers was reported (69%) to be a major reason for which symposia was not preferred. CONCLUSION: This study concluded that while planning for health education dissemination in an educated group a focused programme should be formulated in small groups preferably in the form of lectures on specific topics, more so while dealing with participants of higher age group having higher educational qualification

The METEX study: Methotrexate versus expectant management in women with ectopic pregnancy: A randomised controlled trial

Background: Patients with ectopic pregnancy (EP) and low serum hCG concentrations and women with a pregnancy of unknown location (PUL) and plateauing serum hCG levels are commonly treated with systemic methotrexate (MTX). However, there is no evidence that treatment in these particular subgroups of women is necessary as many of these early EPs may resolve spontaneously. The aim of this study is whether expectant management in women with EP or PUL and with low but plateauing serum hCG concentrations is an alternative to MTX treatment in terms of treatment success, future pregnancy, health related quality of life and costs. Methods/Design: A multicentre randomised controlled trial in TheNetherlands. Hemodynamically stable patients with an EP visible on transvaginal ultrasound and a plateauing serum hCG concentration < 1,500 IU/L or with a persisting PUL with plateauing serum hCG concentrations < 2,000 IU/L are eligible for the trial. Patients with a viable EP, signs of tubal rupture/abdominal bleeding, or a contra-indication for MTX will not be included. Expectant management is compared with systemic MTX in a single dose intramuscular regimen (1 mg/ kg) in an outpatient setting. Serum hCG levels are monitored weekly; in case of inadequately declining, systemic MTX is installed or continued. In case of hemodynamic instability and/or signs of tubal rupture, surgery is performed. The primary outcome measure is an uneventful decline of serum hCG to an undetectable level by the initial intervention. Secondary outcomes are (re)interventions (additional systemic MTX injections and/or surgery), treatment complications, health related quality of life, financial costs, and future fertility. Analysis is performed according to the intention to treat principle. Quality of life is assessed by questionnaires before and at three time points after randomisation. Costs are expressed as direct costs with data on costs and used resources in the participating centres. Fertility is assessed by questionnaires after 6, 12, 18 and 24 months. Patients' preferences will be assessed using a discrete choice experiment. Discussion: This trial will provide guidance on the present management dilemmas in women with EPs and PULs with low and plateauing serum hCG concentrations

The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence

Funding: This work was funded by the European Research Council [http://erc.europa.eu/], AJPB (STRIFE Advanced Grant; C-2009-AdG-249793). The work was also supported by: the Wellcome Trust [www.wellcome.ac.uk], AJPB (080088, 097377); the UK Biotechnology and Biological Research Council [www.bbsrc.ac.uk], AJPB (BB/F00513X/1, BB/K017365/1); the CNPq-Brazil [http://cnpq.br], GMA (Science without Borders fellowship 202976/2014-9); and the National Centre for the Replacement, Refinement and Reduction of Animals in Research [www.nc3rs.org.uk], DMM (NC/K000306/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgments We thank Dr. Elizabeth Johnson (Mycology Reference Laboratory, Bristol) for providing strains, and the Aberdeen Proteomics facility for the biotyping of S. cerevisiae clinical isolates, and to Euroscarf for providing S. cerevisiae strains and plasmids. We are grateful to our Microscopy Facility in the Institute of Medical Sciences for their expert help with the electron microscopy, and to our friends in the Aberdeen Fungal Group for insightful discussions.Peer reviewedPublisher PD

Interferon-Gamma Release Assay (Modified QuantiFERON) as a Potential Marker of Infection for Leishmania donovani, a Proof of Concept Study

Visceral leishmaniasis is caused by a parasite of the Leishmania species, but infection does not always lead to overt clinical disease. To detect infection, the Montenegro test or Leishmanin Skin Test (LST) is used along with serological markers. The LST is a test of the delayed-type hypersensitivity response read 48–72 hours after intradermal injection of leishmanin antigen. LST has many drawbacks, as complex administration and reading, boosting of anamnestic immune responses and difficult sourcing of GMP-compliant product and alternative tools for epidemiological research are badly needed. We evaluated whether a Interferon-γ Release Assay based on the QuantiFERON-TB test format, which was approved by the Food and Drug Administration (FDA) as a test for detecting latent Mycobacterium tuberculosis infection, could become an in vitro diagnostic aid for the measurement of cell-mediated immune reactivity against L.donovani. We obtained good results with one of five of the antigens we evaluated and confirm the potential of this assay

Risk management of biosimilars in oncology: each medicine is a work in progress

Drug licensing and drug safety monitoring for standard chemical entities have been established and are routinely used. These have resulted in a solid foundation of knowledge from which confident therapeutic decisions can be made. For many chemical entities, this advanced level of experience is also present for the generic products. The expertise surrounding the development of biosimilar competitor versions is increasing and progress is encouraging. To address the re-engineering and comparability complexities of biosimilars, the European Union imposed a requirement that risk management plans be included in the medications’ marketing applications. This paper summarizes and discusses the circumstances complicating the public’s view of drug safety, historical incidents during the transition from innovative to competitor products, as well as retrospective assessments of the development and post-marketing experiences thus far with two biosimilars. Through assessing the market entries and post-marketing experiences of biosimilars used in oncology, the healthcare field can better prepare for the next wave of comparator-products: biosimilar monoclonal antibodies

A perspective on the measurement of time in plant disease epidemiology

The growth and development of plant pathogens and their hosts generally respond strongly to the temperature of their environment. However, most studies of plant pathology record pathogen/host measurements against physical time (e.g. hours or days) rather than thermal time (e.g. degree-days or degree-hours). This confounds the comparison of epidemiological measurements across experiments and limits the value of the scientific literature

A randomised clinical trial on cardiotocography plus fetal blood sampling versus cardiotocography plus ST-analysis of the fetal electrocardiogram (STAN®) for intrapartum monitoring

<p>Abstract</p> <p>Background</p> <p>Cardiotocography (CTG) is worldwide the method for fetal surveillance during labour. However, CTG alone shows many false positive test results and without fetal blood sampling (FBS), it results in an increase in operative deliveries without improvement of fetal outcome. FBS requires additional expertise, is invasive and has often to be repeated during labour. Two clinical trials have shown that a combination of CTG and ST-analysis of the fetal electrocardiogram (ECG) reduces the rates of metabolic acidosis and instrumental delivery. However, in both trials FBS was still performed in the ST-analysis arm, and it is therefore still unknown if the observed results were indeed due to the ST-analysis or to the use of FBS in combination with ST-analysis.</p> <p>Methods/Design</p> <p>We aim to evaluate the effectiveness of non-invasive monitoring (CTG + ST-analysis) as compared to normal care (CTG + FBS), in a multicentre randomised clinical trial setting. Secondary aims are: 1) to judge whether ST-analysis of fetal electrocardiogram can significantly decrease frequency of performance of FBS or even replace it; 2) perform a cost analysis to establish the economic impact of the two treatment options.</p> <p>Women in labour with a gestational age ≥ 36 weeks and an indication for CTG-monitoring can be included in the trial.</p> <p>Eligible women will be randomised for fetal surveillance with CTG and, if necessary, FBS or CTG combined with ST-analysis of the fetal ECG.</p> <p>The primary outcome of the study is the incidence of serious metabolic acidosis (defined as pH < 7.05 and Bd_ecf> 12 mmol/L in the umbilical cord artery). Secondary outcome measures are: instrumental delivery, neonatal outcome (Apgar score, admission to a neonatal ward), incidence of performance of FBS in both arms and cost-effectiveness of both monitoring strategies across hospitals.</p> <p>The analysis will follow the intention to treat principle. The incidence of metabolic acidosis will be compared across both groups. Assuming a reduction of metabolic acidosis from 3.5% to 2.1 %, using a two-sided test with an alpha of 0.05 and a power of 0.80, in favour of CTG plus ST-analysis, about 5100 women have to be randomised. Furthermore, the cost-effectiveness of CTG and ST-analysis as compared to CTG and FBS will be studied.</p> <p>Discussion</p> <p>This study will provide data about the use of intrapartum ST-analysis with a strict protocol for performance of FBS to limit its incidence. We aim to clarify to what extent intrapartum ST-analysis can be used without the performance of FBS and in which cases FBS is still needed.</p> <p>Trial Registration Number</p> <p>ISRCTN95732366</p

Progestogens to prevent preterm birth in twin pregnancies: an individual participant data meta-analysis of randomized trials

<p>Abstract</p> <p>Background</p> <p>Preterm birth is the principal factor contributing to adverse outcomes in multiple pregnancies. Randomized controlled trials of progestogens to prevent preterm birth in twin pregnancies have shown no clear benefits. However, individual studies have not had sufficient power to evaluate potential benefits in women at particular high risk of early delivery (for example, women with a previous preterm birth or short cervix) or to determine adverse effects for rare outcomes such as intrauterine death.</p> <p>Methods/design</p> <p>We propose an individual participant data meta-analysis of high quality randomized, double-blind, placebo-controlled trials of progestogen treatment in women with a twin pregnancy. The primary outcome will be adverse perinatal outcome (a composite measure of perinatal mortality and significant neonatal morbidity). Missing data will be imputed within each original study, before data of the individual studies are pooled. The effects of 17-hydroxyprogesterone caproate or vaginal progesterone treatment in women with twin pregnancies will be estimated by means of a random effects log-binomial model. Analyses will be adjusted for variables used in stratified randomization as appropriate. Pre-specified subgroup analysis will be performed to explore the effect of progestogen treatment in high-risk groups.</p> <p>Discussion</p> <p>Combining individual patient data from different randomized trials has potential to provide valuable, clinically useful information regarding the benefits and potential harms of progestogens in women with twin pregnancy overall and in relevant subgroups.</p