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

Safety Climate in Organizations

Safety climate is a collective construct derived from individuals' shared perceptions of the various ways that safety is valued in the workplace. Research over the past 35 years shows that safety climate is an important predictor of safety behavior and safety outcomes such as accidents and injury. We first review the conceptual foundations of safety climate and explore how the construct can be applied to different levels of analysis. We then review ways that safety climate influences individual processes of sense making, motivation, and work behavior. Next, we explore the impact of safety climate on organization-level outcomes related to both safety and productivity. We conclude with suggestions for future research and practice to support the overall safety of people and organizations

Decline in breast cancer incidence due to removal of promoter: combination estrogen plus progestin

Combination estrogen plus progestin causes breast cancer. In light of this causal relation, the rapid decline in breast cancer incidence noted in 2003, following an earlier and slower reduction in incidence from 1999, raises important issues regarding the proportion of this decline that may be due to a reduction in the use of combination therapy by postmenopausal women. The context of these national trends is reviewed and the strong link to the use of hormone therapy is discussed, after noting that screening cannot explain any substantial component of these trends. The rapid decrease in incidence, most evident among women aged 50 to 69 years and in estrogen receptor positive tumors, that parallels the decline in combination hormone use is consistent with a promoter effect for estrogen plus progestins

A novel method for measuring patients' adherence to insulin dosing guidelines: introducing indicators of adherence

<p>Abstract</p> <p>Background</p> <p>Diabetic type 1 patients are often advised to use dose adjustment guidelines to calculate their doses of insulin. Conventional methods of measuring patients' adherence are not applicable to these cases, because insulin doses are not determined in advance. We propose a method and a number of indicators to measure patients' conformance to these insulin dosing guidelines.</p> <p>Methods</p> <p>We used a database of logbooks of type 1 diabetic patients who participated in a summer camp. Patients used a guideline to calculate the doses of insulin lispro and glargine four times a day, and registered their injected doses in the database. We implemented the guideline in a computer system to calculate recommended doses. We then compared injected and recommended doses by using five indicators that we designed for this purpose: absolute agreement (AA): the two doses are the same; relative agreement (RA): there is a slight difference between them; extreme disagreement (ED): the administered and recommended doses are merely opposite; Under-treatment (UT) and over-treatment (OT): the injected dose is not enough or too high, respectively. We used weighted linear regression model to study the evolution of these indicators over time.</p> <p>Results</p> <p>We analyzed 1656 insulin doses injected by 28 patients during a three weeks camp. Overall indicator rates were AA = 45%, RA = 30%, ED = 2%, UT = 26% and OT = 30%. The highest rate of absolute agreement is obtained for insulin glargine (AA = 70%). One patient with alarming behavior (AA = 29%, RA = 24% and ED = 8%) was detected. The monitoring of these indicators over time revealed a crescendo curve of adherence rate which fitted well in a weighted linear model (slope = 0.85, significance = 0.002). This shows an improvement in the quality of therapeutic decision-making of patients during the camp.</p> <p>Conclusion</p> <p>Our method allowed the measurement of patients' adherence to their insulin adjustment guidelines. The indicators that we introduced were capable of providing quantitative data on the quality of patients' decision-making for the studied population as a whole, for each individual patient, for all injections, and for each time of injection separately. They can be implemented in monitoring systems to detect non-adherent patients.</p

Non-fullerene acceptor photostability and its impact on organic solar cell lifetime

The development of non-fullerene acceptors (NFAs) has facilitated the realization of efficient organic solar cells (OSCs) with minimal burn-in losses and excellent long-term stability. However, the role of NFA molecular structures on device stability remains unclear, limiting commercialization of NFA-based OSCs. Herein, the photostability of 10 OSC devices, fabricated with various NFAs (O-IDTBR, EH-IDTBR, ITIC, and ITIC-M) blended with donor polymers (PTB7-Th, PffBT4T-2OD, and PBDB-T), is investigated. O-IDTBR and EH-IDTBR form highly stable devices with all three polymers, whereas ITIC and ITIC-M devices suffer from burn-in losses and long-term degradation. Conformational instability is found to be responsible for the poor photostability of ITIC and ITIC-M, resulting in poor device stability. Twisting and potential breakage of the chemical bond that links the end group to the main backbone of ITIC and ITIC-M molecules causes undesirable conformational changes. Potential strategies to overcome such detrimental photo-induced conformational changes in NFAs are proposed

Change in bias in self-reported body mass index in Australia between 1995 and 2008 and the evaluation of correction equations

<p>Abstract</p> <p>Background</p> <p>Many studies have documented the bias in body mass index (BMI) determined from self-reported data on height and weight, but few have examined the change in bias over time.</p> <p>Methods</p> <p>Using data from large, nationally-representative population health surveys, we examined change in bias in height and weight reporting among Australian adults between 1995 and 2008. Our study dataset included 9,635 men and women in 1995 and 9,141 in 2007-2008. We investigated the determinants of the bias and derived correction equations using 2007-2008 data, which can be applied when only self-reported anthropometric data are available.</p> <p>Results</p> <p>In 1995, self-reported BMI (derived from height and weight) was 1.2 units (men) and 1.4 units (women) lower than measured BMI. In 2007-2008, there was still underreporting, but the amount had declined to 0.6 units (men) and 0.7 units (women) below measured BMI. The major determinants of reporting error in 2007-2008 were age, sex, measured BMI, and education of the respondent. Correction equations for height and weight derived from 2007-2008 data and applied to self-reported data were able to adjust for the bias and were accurate across all age and sex strata.</p> <p>Conclusions</p> <p>The diminishing reporting bias in BMI in Australia means that correction equations derived from 2007-2008 data may not be transferable to earlier self-reported data. Second, predictions of future overweight and obesity in Australia based on trends in self-reported information are likely to be inaccurate, as the change in reporting bias will affect the apparent increase in self-reported obesity prevalence.</p

Age-period-cohort modelling of non-Hodgkin's lymphoma incidence in a French region: a period effect compatible with an environmental exposure

<p>Abstract</p> <p>Background</p> <p>The incidence of non-Hodgkin's lymphoma (NHL) has risen steadily during the last few decades in all geographic regions covered by cancer registration for reasons that remain unknown. The aims of this study were to assess the relative contributions of age, period and cohort effects to NHL incidence patterns and therefore to provide clues to explain the increasing incidence.</p> <p>Methods</p> <p>Population and NHL incidence data were provided for the Doubs region (France) during the 1980-2005 period. NHL counts and person-years were tabulated into one-year classes by age (from 20 to 89) and calendar time period. Age-period-cohort models with parametric smooth functions (natural splines) were fitted to the data by assuming a Poisson distribution for the observed number of NHL cases.</p> <p>Results</p> <p>The age-standardised incidence rate increased from 4.7 in 1980 to 11.9 per 100,000 person-years at risk in 1992 (corresponding to a 2.5-fold increase) and stabilised afterwards (11.1 per 100,000 in 2005). Age effects showed a steadily increasing slope up to the age of 80 and levelled off for older ages. Large period curvature effects, both adjusted for cohort effects and non-adjusted (p < 10^-4and p < 10^-5, respectively), showed departure from linear periodic trends; period effects jumped markedly in 1983 and stabilised in 1992 after a 2.4-fold increase (compared to the 1980 period). In both the age-period-cohort model and the age-cohort model, cohort curvature effects were not statistically significant (p = 0.46 and p = 0.08, respectively).</p> <p>Conclusions</p> <p>The increased NHL incidence in the Doubs region is mostly dependent on factors associated with age and calendar periods instead of cohorts. We found evidence for a levelling off in both incidence rates and period effects beginning in 1992. It is unlikely that the changes in classification (which occurred after 1995) and the improvements of diagnostic accuracy could largely account for the 1983-1992 period-effect increase, giving way to an increased exposure to widely distributed risk factors including persistent organic pollutants and pesticides. Continued NHL incidence and careful analysis of period effects are of utmost importance to elucidate the enigmatic epidemiology of NHL.</p