Metformin for endometrial hyperplasia.

BACKGROUND: Endometrial cancer is one of the most common gynaecological cancers in the world. Rates of endometrial cancer are rising, in part because of rising obesity rates. Endometrial hyperplasia is a precancerous condition in women that can lead to endometrial cancer if left untreated. Endometrial hyperplasia occurs more commonly than endometrial cancer. Progesterone tablets that are currently used to treat women with endometrial hyperplasia are associated with adverse effects in up to 84% of women. A levonorgestrel intrauterine device may improve compliance, but it is invasive, is not acceptable to all women, and is associated with irregular vaginal bleeding in 82% of cases. Therefore, an alternative treatment for women with endometrial hyperplasia is needed. Metformin, a drug that is often used to treat people with diabetes, has been shown, in some human studies, to reverse endometrial hyperplasia. However, the effectiveness and safety of metformin for treatment of endometrial hyperplasia remain uncertain. This is an update of a review first published in 2017. OBJECTIVES: To determine the effectiveness and safety of metformin in treating women with endometrial hyperplasia. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, PubMed, Embase, Google Scholar, OpenGrey, LILACS, and two trials registers from inception to 5 September 2022. We searched the bibliographies of all relevant studies, and contacted experts in the field for any additional trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cross-over trials comparing metformin (used alone or in combination with other medical therapies) versus placebo, no treatment, any conventional medical treatment, or any other active intervention for women with histologically confirmed endometrial hyperplasia of any type. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility, extracted data from included studies, assessed the risk of bias in the included studies, and assessed the certainty of the evidence for each outcome. We resolved disagreements by discussion or by deferring to a third review author. When study details were missing, review authors contacted the study authors. The primary outcome of this review was regression of endometrial hyperplasia histology (with or without atypia) towards normal histology. MAIN RESULTS: We included seven RCTs, in which a total of 387 women took part. In the comparison, Metformin plus megestrol versus megestrol alone, we rated the certainty of the evidence as low for the outcome, regression of endometrial hyperplasia. We rated the quality of the evidence as very low for the rest of the outcomes, in all three comparisons. Although there was a low risk of selection bias, there was a high risk of bias in the blinding of personnel and outcome assessment (performance bias and detection bias) in many studies. This update identified four new RCTs and six ongoing RCTs. Metformin versus megestrol We are uncertain whether metformin increases the regression of endometrial hyperplasia towards normal histology over megestrol (odds ratio (OR) 4.89, 95% confidence interval (CI) 1.56 to 15.32; P = 0.006; 2 RCTs, 83 participants; I² = 7%; very low-certainty evidence). This evidence suggests that if the rate of regression with megestrol is 61%, the rate of regression with metformin would be between 71% and 96%. It is unresolved whether metformin results in different rates of abnormal uterine bleeding or hysterectomy compared to megestrol. No study in this comparison reported progression of hyperplasia to endometrial cancer, recurrence of endometrial hyperplasia, health-related quality of life, or adverse effects during treatment. Metformin plus megestrol versus megestrol monotherapy The combination of metformin and megestrol may enhance the regression of endometrial hyperplasia towards normal histology more than megestrol alone (OR 3.27, 95% CI 1.65 to 6.51; P = 0.0007; 4 RCTs, 258 participants; I² = 0%, low-certainty evidence). This suggests that if the rate of regression with megestrol monotherapy is 54%, the rate of regression with the addition of metformin would be between 66% and 84%. In one study, 3/8 (37.5%) of participants who took metformin had nausea that settled without further treatment. It is unresolved whether the combination of metformin and megestrol results in different rates of recurrence of endometrial hyperplasia, progression of endometrial hyperplasia to endometrial cancer, or hysterectomy compared to megestrol monotherapy. No study in this comparison reported abnormal uterine bleeding, or health-related quality of life. Metformin plus levonorgestrel (intrauterine system) versus levonorgestrel (intrauterine system) monotherapy We are uncertain whether there is a difference between groups in the regression of endometrial hyperplasia towards normal histology (OR 0.29, 95% CI 0.01 to 7.56; 1 RCT, 46 participants; very low-certainty evidence). This evidence suggests that if the rate of regression with levonorgestrel monotherapy is 96%, the rate of regression with the addition of metformin would be between 73% and 100%. It is unresolved whether the combination of metformin and levonorgestrel results in different rates of abnormal uterine bleeding, hysterectomy, or the development of adverse effects during treatment compared to levonorgestrel monotherapy. No study in this comparison reported recurrence of endometrial hyperplasia, progression of hyperplasia to endometrial cancer, or health-related quality of life. AUTHORS' CONCLUSIONS: Review authors found insufficient evidence to either support or refute the use of metformin, specifically megestrol acetate, given alone or in combination with standard therapy, for the treatment of women with endometrial hyperplasia. Robustly designed and adequately powered randomised controlled trials, yielding long-term outcome data are still needed to address this clinical question.

Protocol for the INFORMED (Individualised Patient Care and Treatment for Maternal Diabetes) Study: a randomised controlled trial embedded within routine care.

INTRODUCTION: Diabetes in pregnancy presents a unique physiological challenge to manage glycaemia while maintaining adequate nourishment for the growing fetus. Women with diabetes who become pregnant are at greater risk of adverse maternal and newborn outcomes, compared with women without diabetes. Evidence suggests that control of (postprandial) glycaemia is key to manage maternal and offspring health but it is not yet clear (1) how diet and lifestyle moderate these shifts across the full duration of pregnancy or (2) what aspects of maternal and offspring health are associated with dysglycaemia. METHODS AND ANALYSIS: To investigate these gaps, a cross-over randomised clinical trial has been embedded within routine clinical care. Seventy-six pregnant women in their first trimester with type 1 or type 2 diabetes (with or without medication) attending their routine antenatal appointments at National Health Service (NHS) Leeds Teaching Hospitals will be recruited. Following informed consent, data on women's health, glycaemia, pregnancy and delivery will be shared by the NHS with researchers. At each visit in the first (10-12 weeks), second (18-20 weeks) and third (28-34 weeks) trimester, participants will be asked for consent to: (1) lifestyle and diet questionnaires, (2) blood for research purposes and (3) analysis of urine collected at clinical visits. Additionally, participants will be asked to consume two blinded meals in duplicate in second and third trimester. Glycaemia will be assessed by continuous glucose monitoring as part of routine care. The primary outcome is the effect of experimental meals (high vs low protein) on postprandial glycaemia. Secondary outcomes include (1) the association between dysglycaemia and maternal and newborn health, and (2) the association between maternal metabolic profiles in early pregnancy with dysglycaemia in later pregnancy. ETHICS AND DISSEMINATION: The Leeds East Research Ethics Committee and NHS (REC: 21/NE/0196) approved the study. Results will be published in peer-reviewed journals and disseminated to participants and the wider public. TRIAL REGISTRATION NUMBER: ISRCTN57579163.

Safety and efficacy of intrauterine balloon tamponade vs uterine gauze packing in managing postpartum hemorrhage: A systematic review and meta-analysis.

BACKGROUND: There is debate on whether uterine gauze packing or intrauterine balloon tamponade is safer and more effective as a surgical management option for treating postpartum hemorrhage. OBJECTIVE: This study aimed to compare intra- and postoperative outcomes of intrauterine balloon tamponade and uterine gauze packing in patients with postpartum hemorrhage. STUDY DESIGN: A range of databases such as Cochrane and PubMed were searched using terms including "post-partum haemorrhage," "uterine balloon tamponade," and "uterine gauze packing." All observational studies comparing intrauterine balloon tamponade with uterine gauze packing were included. Five studies were identified enrolling 821 adult patients diagnosed with postpartum hemorrhage. Primary outcomes included blood loss volume, success rates, and maternal mortality. Secondary outcomes comprised requiring additional interventions, postoperative hemoglobin levels, and requiring blood transfusions. Fixed and random models were used for analysis. RESULTS: Intrauterine balloon tamponade seemed to be a superior option to uterine gauze packing. Intrauterine balloon tamponade was better in reducing intraoperative blood loss, with a statistically significant improvement (P<.0001). Cases managed with intrauterine balloon tamponade seemed to have statistically significant shorter operative time (P=.023) and hospital length of stay (P=.020) in one study. CONCLUSION: Intrauterine balloon tamponade remains more effective and safer as a first-line surgical management option for postpartum hemorrhage compared with uterine gauze packing.

The evaluation of an e-learning prescribing course for general practice.

Prescribed medication may lead to significant morbidity or mortality as a result of these medications causing adverse events, or because of a prescribing error. E-learning is a common tool used in supporting training in prescribing. This paper describes the development of an e-learning course and the subsequent evaluation undertaken by the users with the aim of obtaining an effective e-learning course for prescribing. The e-learning course was developed by general practitioners and pharmacists and focussed on the principles of good prescribing, examined the common reasons for prescribing errors, and was evaluated using self-reported quantitative and qualitative measures. Scores significantly increased on an assessment given before and after the course. The majority of respondents reported that the e-learning course had a positive impact on prescribing knowledge, skills and attitudes, with medication reviews the top area where a change in prescribing practice was reported. Over 90% of the respondents agreed that the e-learning course was easy to use and a useful part of their continuing professional education. This study shows that clinicians recognise the on-going need for training in prescribing, but the lack of training is one of the factors contributing to errors, which suggests that more education is needed, not just for GPs in training, but for qualified GPs as well.

A qualitative evaluation of a prescribing e-learning package for general practice.

BACKGROUND: The GMC PRACtiCe study identified a 1 in 20 error rate in prescriptions issued in general practice and identified a need for further training in prescribing. As a result, an e-Learning prescribing package was designed and launched to healthcare professionals through the Royal College of General Practitioners in January 2014. AIM: This part of the study explored the longer-term impact on prescribing knowledge, attitudes and behaviours of practitioners completing the eLearning prescribing package. METHOD: On completion of the e-Learning package, participants were asked to indicate their willingness to be contacted for a telephone interview. Semi-structured interviews were conducted which were audio recorded, transcribed verbatim and analysed using thematic analysis, aided by NVivo. Interviewees were invited to enter a prize draw to win Stockley's Drug Interaction textbook (provided courtesy of the Royal Pharmaceutical Society). RESULTS: Of the 120 participants who expressed an interest in being followed up for interview, seven prescribers were interviewed in 2014 and 2015. Reasons for completing the course were explored, and interviewees gave examples of changes made to their prescribing practice as a result of completing the e-Learning. This included the adoption of specific strategies to enhance safe practice, and enacting enhanced vigilance in key areas such as renal function monitoring. Some changes to the course content and presentation were also recommended. CONCLUSION: These interviews have highlighted the potential for using e-Learning for prescribing training and to achieve long-term changes in prescribing practice. However, further work is needed to generate substantive evidence of its impact on prescribing.

Metformin for endometrial hyperplasia.

BACKGROUND: Endometrial cancer is one of the most common gynaecological cancers in the world. Rates of endometrial cancer are rising, in part because of rising obesity rates. Endometrial hyperplasia is a precancerous condition in women that can lead to endometrial cancer if left untreated. Endometrial hyperplasia occurs more commonly than endometrial cancer. Progesterone tablets currently used to treat women with endometrial hyperplasia are associated with adverse effects in up to 84% of women. The levonorgestrel intrauterine device (Mirena Coil, Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ, USA) may improve compliance, but it is invasive, is not acceptable to all women, and is associated with irregular vaginal bleeding in 82% of cases. Therefore, an alternative treatment for women with endometrial hyperplasia is needed. Metformin, a drug that is often used to treat people with diabetes, has been shown in some human studies to reverse endometrial hyperplasia. However, the effectiveness and safety of metformin for treatment of endometrial hyperplasia remain uncertain. OBJECTIVES: To determine the effectiveness and safety of metformin in treating women with endometrial hyperplasia. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, Google Scholar, OpenGrey, Latin American Caribbean Health Sciences Literature (LILACS), and two trials registers from inception to 10 January 2017. We searched the bibliographies of all included studies and reviews on this topic. We also handsearched the conference abstracts of the European Society of Human Reproduction and Embryology (ESHRE) 2015 and the American Society for Reproductive Medicine (ASRM) 2015. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cross-over trials comparing metformin (used alone or in combination with other medical therapies) versus placebo or no treatment, any conventional medical treatment, or any other active intervention for women with histologically confirmed endometrial hyperplasia of any type. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility, extracted data from included studies, and assessed the risk of bias of included studies. We resolved disagreements by discussion or by deferment to a third review author. When study details were missing, review authors contacted study authors. The primary outcome of this review was regression of endometrial hyperplasia histology (with or without atypia) towards normal histology. Secondary outcome measures included recurrence of endometrial hyperplasia, progression of endometrial hyperplasia to endometrial cancer, hysterectomy rate, abnormal uterine bleeding, health-related quality of life, and adverse effects during treatment. MAIN RESULTS: We included three RCTs in which a total of 77 women took part. We rated the quality of the evidence as very low for all outcomes owing to very serious risk of bias (associated with poor reporting, attrition, and limitations in study design) and imprecision.We performed a meta-analysis of two trials with 59 participants. When metformin was compared with megestrol acetate in women with endometrial hyperplasia, we found insufficient evidence to determine whether there were differences between groups for the following outcomes: regression of endometrial hyperplasia histology towards normal histology (odds ratio (OR) 3.34, 95% confidence interval (CI) 0.97 to 11.57, two RCTs, n = 59, very low-quality evidence), hysterectomy rates (OR 0.91, 95% CI 0.05 to 15.52, two RCTs, n = 59, very low-quality evidence), and rates of abnormal uterine bleeding (OR 0.91, 95% CI 0.05 to 15.52, two RCTs, n = 44 , very low-quality evidence). We found no data for recurrence of endometrial hyperplasia or health-related quality of life. Both studies (n = 59) provided data on progression of endometrial hyperplasia to endometrial cancer as well as one (n = 16) reporting some adverse effects in the metformin arm, notably nausea, thrombosis, lactic acidosis, abnormal liver and renal function among others.Another trial including 16 participants compared metformin plus megestrol acetate versus megestrol acetate alone in women with endometrial hyperplasia. We found insufficient evidence to determine whether there were differences between groups for the following outcomes: regression of endometrial hyperplasia histology towards normal histology (OR 9.00, 95% CI 0.94 to 86.52, one RCT, n = 16, very low-quality evidence), recurrence of endometrial hyperplasia among women who achieve regression (OR not estimable, no events recorded, one RCT, n = 8, very low-quality evidence), progression of endometrial hyperplasia to endometrial cancer (OR not estimable, no events recorded, one RCT, n = 13, very low-quality evidence), or hysterectomy rates (OR 0.29, 95% CI 0.01 to 8.37, one RCT, n = 16, very low-quality evidence). Investigators provided no data on abnormal uterine bleeding or health-related quality of life. In terms of adverse effects, three of eight participants (37.5%) in the metformin plus megestrol acetate study arm reported nausea. AUTHORS' CONCLUSIONS: At present, evidence is insufficient to support or refute the use of metformin alone or in combination with standard therapy - specifically, megestrol acetate - versus megestrol acetate alone, for treatment of endometrial hyperplasia. Robustly designed and adequately powered randomised controlled trials yielding long-term outcome data are needed to address this clinical question.

Methylation Profiling RIN3 and MEF2C Identifies Epigenetic Marks Associated with Sporadic Early Onset Alzheimer's Disease.

A number of genetic loci associate with early onset Alzheimer's disease (EOAD); however, the drivers of this disease remains enigmatic. Genome wide association and in vivo modeling have shown that loss-of-function, e.g., ABCA7, reduced levels of SIRT1 and MEFF2C, or increased levels of PTK2ß confer risk or link to the pathogenies. It is known that DNA methylation can profoundly affect gene expression and can impact on the composition of the proteome; therefore, the aim of this study is to assess if genes associated with sporadic EOAD (sEOAD) are differentially methylated. Epi-profiles of DNA extracted from blood and cortex were compared using a pyrosequencing platform. We identified significant group-wide hypomethylation in AD blood when compared to controls for 7 CpGs located within the 3'UTR of RIN3 (CpG1 p = 0.019, CpG2 p = 0.018, CpG3 p = 0.012, CpG4 p = 0.009, CpG5 p = 0.002, CpG6 p = 0.018, and CpG7 p = 0.013, respectively; AD/Control n = 22/26; Male/Female n = 27/21). Observed effects were not gender specific. No group wide significant differences were found in the promoter methylation of PTK2ß, ABCA7, SIRT1, or MEF2C, genes known to associate with late onset AD. A rare and significant difference in methylation was observed for one CpG located upstream of the MEF2C promoter in one AD individual only (22% reduction in methylation, p = 2.0E-10; Control n = 26, AD n = 25, Male/Female n = 29/22). It is plausible aberrant methylation may mark sEOAD in blood and may manifest in some individuals as rare epi-variants for genes linked to sEOAD.

Mutation analysis of sporadic early-onset Alzheimer's disease using the NeuroX array.

We have screened sporadic early-onset Alzheimer's disease (sEOAD, n = 408) samples using the NeuroX array for known causative and predicted pathogenic variants in 16 genes linked to familial forms of neurodegeneration. We found 2 sEOAD individuals harboring a known causative variant in PARK2 known to cause early-onset Parkinson's disease; p.T240M (n = 1) and p.Q34fs delAG (n = 1). In addition, we identified 3 sEOAD individuals harboring a predicted pathogenic variant in MAPT (p.A469T), which has previously been associated with AD. It is currently unknown if these variants affect susceptibility to sEOAD, further studies would be needed to establish this. This work highlights the need to screen sEOAD individuals for variants that are more classically attributed to other forms of neurodegeneration.

Metformin for endometrial hyperplasia: a Cochrane protocol.

INTRODUCTION: Endometrial hyperplasia is a precancerous lesion of the endometrium, commonly presenting with uterine bleeding. If managed expectantly, it frequently progresses to endometrial carcinoma, rates of which are increasing dramatically worldwide. However, the established treatment for endometrial hyperplasia (progestogens) involves multiple side effects and leaves the risk of recurrence. Metformin is the most commonly used oral hypoglycaemic agent in type 2 diabetes mellitus. It has also been linked to the reversal of endometrial hyperplasia and may therefore contribute to decreasing the prevalence of endometrial carcinoma without the fertility and side effect consequences of current therapies. However, the efficacy and safety of metformin being used for this therapeutic target is unclear and, therefore, this systematic review will aim to determine this. METHODS AND ANALYSIS: We will search the following trials and databases with no language restrictions: Cochrane Gynaecology and Fertility Specialised Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; EBSCO Cumulative Index to Nursing and Allied Health Literature; PubMed; Google Scholar; ClinicalTrials.gov; the WHO International Trials Registry Platform portal; OpenGrey and the Latin American and Caribbean Health Sciences Literature (LILACS). We will include randomised controlled trials (RCTs) of use of metformin compared with a placebo or no treatment, conventional medical treatment (eg, progestogens) or any other active intervention. Two review authors will independently assess the trial eligibility, risk of bias and extract appropriate data points. Trial authors will be contacted for additional data. The primary review outcome is the regression of endometrial hyperplasia histology towards normal histology. Secondary outcomes include hysterectomy rate; abnormal uterine bleeding; quality of life scores and adverse reactions to treatments. ETHICS AND DISSEMINATION: Dissemination of the completed review will be through the Cochrane Library as well as through presenting the results at appropriate conferences.

ABCA7 p.G215S as potential protective factor for Alzheimer's disease.

Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs have led to the discovery of over 20 susceptibility loci for Alzheimer's disease (AD). Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease. We have used exome and genome sequencing data to analyze the single independent and joint effect of rare and low-frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE (BIN1, CLU, CR1, PICALM, MS4A6A, ABCA7, EPHA1, CD33, and CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North-American ancestry. We identified coding variability in ABCA7 as contributing to AD risk. This locus harbors a low-frequency coding variant (p.G215S, rs72973581, minor allele frequency = 4.3%) conferring a modest but statistically significant protection against AD (p-value = 0.024, odds ratio = 0.57, 95% confidence interval = 0.41-0.80). Notably, our results are not driven by an enrichment of loss of function variants in ABCA7, recently reported as main pathogenic factor underlying AD risk at this locus. In summary, our study confirms the role of ABCA7 in AD and provides new insights that should address functional studies.

Screening exons 16 and 17 of the amyloid precursor protein gene in sporadic early-onset Alzheimer's disease.

Early-onset Alzheimer's disease (EOAD) can be familial (FAD) or sporadic EOAD (sEOAD); both have a disease onset ≤65 years of age. A total of 451 sEOAD samples were screened for known causative mutations in exons 16 and 17 of the amyloid precursor protein (APP) gene. Four samples were shown to be heterozygous for 1 of 3 known causative mutations: p.A713T, p.V717I, and p.V717G; this highlights the importance of screening EOAD patients for causative mutations. Additionally, we document an intronic 6 base pair (bp) deletion located 83 bp downstream of exon 17 (rs367709245, IVS17 83-88delAAGTAT), which has a nonsignificantly increased minor allele frequency in our sEOAD cohort (0.006) compared to LOAD (0.002) and controls (0.002). To assess the effect of the 6-bp deletion on splicing, COS-7 and BE(2)-C cells were transfected with a minigene vector encompassing exon 17. There was no change in splicing of exon 17 from constructs containing either wild type or deletion inserts. Sequencing of cDNA generated from cerebellum and temporal cortex of a patient harboring the deletion found no evidence of transcripts with exon 17 removed.

The current provision of community-based teaching in UK medical schools: an online survey and systematic review.

OBJECTIVE: To evaluate the current provision and outcome of community-based education (CBE) in UK medical schools. DESIGN AND DATA SOURCES: An online survey of UK medical school websites and course prospectuses and a systematic review of articles from PubMed and Web of Science were conducted. Articles in the systematic review were assessed using Rossi, Lipsey and Freeman's approach to programme evaluation. STUDY SELECTION: Publications from November 1998 to 2013 containing information related to community teaching in undergraduate medical courses were included. RESULTS: Out of the 32 undergraduate UK medical schools, one was excluded due to the lack of course specifications available online. Analysis of the remaining 31 medical schools showed that a variety of CBE models are utilised in medical schools across the UK. Twenty-eight medical schools (90.3%) provide CBE in some form by the end of the first year of undergraduate training, and 29 medical schools (93.5%) by the end of the second year. From the 1378 references identified, 29 papers met the inclusion criteria for assessment. It was found that CBE mostly provided advantages to students as well as other participants, including GP tutors and patients. However, there were a few concerns regarding the lack of GP tutors' knowledge in specialty areas, the negative impact that CBE may have on the delivery of health service in education settings and the cost of CBE. CONCLUSIONS: Despite the wide variations in implementation, community teaching was found to be mostly beneficial. To ensure the relevance of CBE for 'Tomorrow's Doctors', a national framework should be established, and solutions sought to reduce the impact of the challenges within CBE. STRENGTHS AND LIMITATIONS OF THIS STUDY: This is the first study to review how community-based education is currently provided throughout Medical Schools in the UK. The use of Rossi, Lipsey and Freeman's method of programme evaluation means that the literature was analysed in a consistent and comprehensive way. However, a weakness is that data from the online survey was obtained from online medical school prospectuses. This means the data may be incomplete or out of date. Data in the literature review may also be skewed by publication bias.