Clinical effectiveness and safety of time-lapse imaging systems for embryo incubation and selection in in-vitro fertilisation treatment (TILT): a multicentre, three-parallel-group, double-blind, randomised controlled trial.

BACKGROUND: Time-lapse imaging systems for embryo incubation and selection might improve outcomes of in-vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) treatment due to undisturbed embryo culture conditions, improved embryo selection, or both. However, the benefit remains uncertain. We aimed to evaluate the effectiveness of time-lapse imaging systems providing undisturbed culture and embryo selection, and time-lapse imaging systems providing only undisturbed culture, and compared each with standard care without time-lapse imaging. METHODS: We conducted a multicentre, three-parallel-group, double-blind, randomised controlled trial in participants undergoing IVF or ICSI at seven IVF centres in the UK and Hong Kong. Embryologists randomly assigned participants using a web-based system, stratified by clinic in a 1:1:1 ratio to the time-lapse imaging system for undisturbed culture and embryo selection (time-lapse imaging group), time-lapse imaging system for undisturbed culture alone (undisturbed culture group), and standard care without time-lapse imaging (control group). Women were required to be aged 18-42 years and men (ie, their partners) 18 years or older. Couples had to be receiving their first, second, or third IVF or ICSI treatment and could not participate if using donor gametes. Participants and trial staff were masked to group assignment, embryologists were not. The primary outcome was live birth. We performed analyses using the intention-to-treat principle and reported the main analysis in participants with primary outcome data available (full analysis set). The trial is registered on the International Trials Registry (ISRCTN17792989) and is now closed. FINDINGS: 1575 participants were randomly assigned to treatment groups (525 participants per group) between June 21, 2018, and Sept 30, 2022. The live birth rates were 33·7% (175/520) in the time-lapse imaging group, 36·6% (189/516) in the undisturbed culture group, and 33·0% (172/522) in the standard care group. The adjusted odds ratio was 1·04 (97·5% CI 0·73 to 1·47) for time-lapse imaging arm versus control and 1·20 (0·85 to 1·70) for undisturbed culture versus control. The risk reduction for the absolute difference was 0·7 percentage points (97·5% CI -5·85 to 7·25) between the time-lapse imaging and standard care groups and 3·6 percentage points (-3·02 to 10·22) between the undisturbed culture and standard care groups. 79 serious adverse events unrelated to the trial were reported (n=28 in time-lapse imaging, n=27 in undisturbed culture, and n=24 in standard care). INTERPRETATION: In women undergoing IVF or ICSI treatment, the use of time-lapse imaging systems for embryo culture and selection does not significantly increase the odds of live birth compared with standard care without time-lapse imaging. FUNDING: Barts Charity, Pharmasure Pharmaceuticals, Hong Kong OG Trust Fund, Hong Kong Health and Medical Research Fund, Hong Kong Matching Fund.

Gestational diabetes mellitus and adverse maternal and perinatal outcomes in twin and singleton pregnancies: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to assess the risk of adverse maternal and perinatal complications between twin and singleton pregnancies affected by gestational diabetes mellitus and the respective group without gestational diabetes mellitus (controls). DATA SOURCES: A literature search was performed using MEDLINE, Embase, and Cochrane from January 1980 to May 2023. STUDY ELIGIBILITY CRITERIA: Observational studies reporting maternal and perinatal outcomes in singleton and/or twin pregnancies with gestational diabetes mellitus vs controls were included. METHODS: This was a systematic review and meta-analysis. Pooled estimate risk ratios with 95% confidence intervals were generated to determine the likelihood of adverse pregnancy outcomes between twin and singleton pregnancies with and without gestational diabetes mellitus. Heterogeneity among studies was evaluated in the model and expressed using the I2 statistic. A P value of <.05 was considered statistically significant. The meta-analyses were performed using Review Manager (RevMan Web). Version 5.4. The Cochrane Collaboration, 2020. Meta-regression was used to compare relative risks between singleton and twin pregnancies. The addition of multiple covariates into the models was used to address the lack of adjustments. RESULTS: Overall, 85 studies in singleton pregnancies and 27 in twin pregnancies were included. In singleton pregnancies with gestational diabetes mellitus, compared with controls, there were increased risks of hypertensive disorders of pregnancy (relative risk, 1.85; 95% confidence interval, 1.69-2.01), induction of labor (relative risk, 1.36; 95% confidence interval, 1.05-1.77), cesarean delivery (relative risk, 1.31; 95% confidence interval, 1.24-1.38), large-for-gestational-age neonate (relative risk, 1.61; 95% confidence interval, 1.46-1.77), preterm birth (relative risk, 1.36; 95% confidence interval, 1.27-1.46), and admission to the neonatal intensive care unit (relative risk, 1.43; 95% confidence interval, 1.38-1.49). In twin pregnancies with gestational diabetes mellitus, compared with controls, there were increased risks of hypertensive disorders of pregnancy (relative risk, 1.69; 95% confidence interval, 1.51-1.90), cesarean delivery (relative risk, 1.10; 95% confidence interval, 1.06-1.13), large-for-gestational-age neonate (relative risk, 1.29; 95% confidence interval, 1.03-1.60), preterm birth (relative risk, 1.19; 95% confidence interval, 1.07-1.32), and admission to the neonatal intensive care unit (relative risk, 1.20; 95% confidence interval, 1.09-1.32) and reduced risks of small-for-gestational-age neonate (relative risk, 0.89; 95% confidence interval, 0.81-0.97) and neonatal death (relative risk, 0.50; 95% confidence interval, 0.39-0.65). When comparing relative risks in singleton vs twin pregnancies, there was sufficient evidence to suggest that twin pregnancies have a lower relative risk of cesarean delivery (P=.003), have sufficient adjustment for confounders, and have lower relative risks of admission to the neonatal intensive care unit (P=.005), stillbirths (P=.002), and neonatal death (P=.001) than singleton pregnancies. CONCLUSION: In both singleton and twin pregnancies, gestational diabetes mellitus was associated with an increased risk of adverse maternal and perinatal outcomes. In twin pregnancies, gestational diabetes mellitus may have a milder effect on some adverse perinatal outcomes and may be associated with a lower risk of neonatal death.

Explaining the UK's 'high-risk' approach to type 2 diabetes prevention: findings from a qualitative interview study with policy-makers in England.

OBJECTIVES: When seeking to prevent type 2 diabetes, a balance must be struck between individual approaches (focusing on people's behaviour 'choices') and population approaches (focusing on the environment in which those choices are made) to address the socioeconomic complexity of diabetes development. We sought to explore how this balance is negotiated in the accounts of policy-makers developing and enacting diabetes prevention policy. METHODS: Twelve semistructured interviews were undertaken with nine UK policy-makers between 2018-2021. We explored their perspectives on disease prevention strategies and what influenced policy decision-making. Interviews were transcribed and analysed thematically using NVIVO. We used Shiffman's political priority framework to theorise why some diabetes prevention policy approaches gather political support while others do not. RESULTS: The distribution of power and funding among relevant actors, and the way they exerted their power determined the dominant approach in diabetes prevention policy. As a result of this distribution, policy-makers framed their accounts of diabetes prevention policies in terms of individual behaviour change, monitoring personal quantitative markers but with limited ability to effect population-level approaches. Such an approach aligns with the current prevailing neoliberal political context, which focuses on individual lifestyle choices to prevent disease rather than on infrastructure measures to improve the environments and contexts within which those choices are made. CONCLUSION: Within new local and national policy structures, there is an opportunity for collaborative working among the National Health Service, local governments and public health teams to balance the focus on disease prevention, addressing upstream drivers of ill health as well as targeting individuals with the highest risk of diabetes.

How do UK general practice staff understand and manage prediabetes? A focus group study.

BACKGROUND: Preventing type 2 diabetes is a national priority; one aspect is the identification and active management of 'prediabetes' through lifestyle change. AIM: To explore what primary care clinicians understood by 'prediabetes', how they communicated this diagnosis to people, how they delivered lifestyle advice, and their views on barriers to lifestyle change. DESIGN & SETTING: Three focus groups were undertaken with 25 individuals from primary care teams (GPs, nurses, and healthcare assistants) in Newham, a deprived and ethnically diverse part of London, UK. METHOD: Recordings were transcribed verbatim and analysed thematically before integrating social and behavioural science theories. RESULTS: Focus groups participants described four main influences on their management of prediabetes in the consultation: social determinants, clinical aspects of diagnosis and management, patient motivation and behaviour change, and long-term care. Since most felt unable to address social determinants such as poverty, discussions with patients tended to focus on attempts to change individual behaviours and achieve particular numerical targets, with limited attention to the social context in which behaviours would play out. CONCLUSION: Type two diabetes prevention efforts in general practice may fail to address the upstream causes of this disease. A narrow focus on numerical targets and decontextualised behaviours overlooks the social complexity of human behaviour and lifestyle choices. Within the consultation, the authors recommend that greater attention is paid to discussing the social context and meaning of particular behaviours. Beyond the consultation, collaboration between primary care clinicians, public health bodies, and local governments is required to address community-level constraints to behaviour change.

General practice in UK newspapers: an empirical analysis of over 400 articles.

BACKGROUND: In the context of the biggest GP workforce crisis since the NHS began, the alleged negative portrayal of UK general practice in the media is often cited as a reason for falling recruitment. AIM: To explore how general practice and GPs are depicted in UK national newspapers. DESIGN AND SETTING: A thematic analysis of all newspaper articles mentioning GPs or general practice published in the UK from late October 2016 to early October 2017 was undertaken, along with a sample of articles on hospital medicine. METHOD: Articles were identified through the Lexin UK search engine; relevant titles were tabulated and data extracted. A preliminary coding scheme was developed through discussion and used to categorise data; additional codes and categories were added iteratively as the analysis progressed. RESULTS: In total, 403 articles on general practice or GPs were identified, and 100 on hospital specialists or specialties were sampled. Articles depicted UK general practice as a service in crisis, with low morale and high burnout, and leaving gaps in patient care. The traditional family doctor service was depicted as rapidly eroding through privatisation and fragmentation, with GPs portrayed as responsible for the crisis and the resulting negative impact on quality of care. Hospital specialties were also illustrated as under pressure, but this crisis was depicted as being the fault of the government. GP leaders interviewed in the press were usually defending their specialty; hospital doctors were usually sharing their expertise. CONCLUSION: Newspaper portrayals of general practice are currently very negative. Efforts to influence the media to provide a more balanced perspective of general practice should continue.

How are health-related behaviours influenced by a diagnosis of pre-diabetes? A meta-narrative review.

BACKGROUND: Several countries, including England, have recently introduced lifestyle-focused diabetes prevention programmes. These aim to reduce the risk of individuals with pre-diabetes developing type 2 diabetes. We sought to summarise research on how socio-cultural influences and risk perception affect people's behaviour (such as engagement in lifestyle interventions) after being told that they have pre-diabetes. METHODS: Using the RAMESES standards for meta-narrative systematic reviews, we identified studies from database searches and citation-tracking. Studies were grouped according to underlying theorisations of pre-diabetes. Following a descriptive analysis, the studies were synthesised with reference to Cockerham's health lifestyle theory. RESULTS: In total, 961 titles were scanned, 110 abstracts assessed and 35 full papers reviewed. Of 15 studies included in the final analysis, 11 were based on individual interviews, focus groups or ethnography and five on structured questionnaires or surveys. Three meta-narratives emerged. The first, which we called biomedical, characterised pre-diabetes as the first stage in a recognised pathophysiological illness trajectory and sought to intervene with lifestyle changes to prevent its progression. The second, which we called psychological, focused on the theory-informed study of the knowledge, attitudes and behaviours in people with pre-diabetes. These studies found that participants generally had an accurate perception of their risk of developing diabetes, but this knowledge did not directly lead to behavioural change. Some psychological studies incorporated wider social factors in their theoretical models and sought to address these through action at the individual level. The third meta-narrative we termed social realist. These studies conceptualised pre-diabetes as the product of social determinants of health and they applied sociological theories to explore the interplay between individual agency and societal influences, such as the socio-cultural context and material and economic circumstances. They recommended measures to address these structural influences on lifestyle choices. CONCLUSIONS: The study of pre-diabetes to date has involved at least three research disciplines (biomedicine, psychology and sociology), which up to now have operated largely independently of one another. Behavioural science and sociology are increasing our understanding of how personal, social, cultural and economic aspects influence health-related behaviours. An interdisciplinary approach with theoretically informed multi-level studies could potentially improve the success of diabetes prevention strategies. TRIAL REGISTRATION: Prospero Registration Number: CRD42018088609 .

Preventing type 2 diabetes: systematic review of studies of cost-effectiveness of lifestyle programmes and metformin, with and without screening, for pre-diabetes.

OBJECTIVE: Explore the cost-effectiveness of lifestyle interventions and metformin in reducing subsequent incidence of type 2 diabetes, both alone and in combination with a screening programme to identify high-risk individuals. DESIGN: Systematic review of economic evaluations. DATA SOURCES AND ELIGIBILITY CRITERIA: Database searches (Embase, Medline, PreMedline, NHS EED) and citation tracking identified economic evaluations of lifestyle interventions or metformin alone or in combination with screening programmes in people at high risk of developing diabetes. The International Society for Pharmaco-economics and Outcomes Research's Questionnaire to Assess Relevance and Credibility of Modelling Studies for Informing Healthcare Decision Making was used to assess study quality. RESULTS: 27 studies were included; all had evaluated lifestyle interventions and 12 also evaluated metformin. Primary studies exhibited considerable heterogeneity in definitions of pre-diabetes and intensity and duration of lifestyle programmes. Lifestyle programmes and metformin appeared to be cost effective in preventing diabetes in high-risk individuals (median incremental cost-effectiveness ratios of £7490/quality-adjusted life-year (QALY) and £8428/QALY, respectively) but economic estimates varied widely between studies. Intervention-only programmes were in general more cost effective than programmes that also included a screening component. The longer the period evaluated, the more cost-effective interventions appeared. In the few studies that evaluated other economic considerations, budget impact of prevention programmes was moderate (0.13%-0.2% of total healthcare budget), financial payoffs were delayed (by 9-14 years) and impact on incident cases of diabetes was limited (0.1%-1.6% reduction). There was insufficient evidence to answer the question of (1) whether lifestyle programmes are more cost effective than metformin or (2) whether low-intensity lifestyle interventions are more cost effective than the more intensive lifestyle programmes that were tested in trials. CONCLUSIONS: The economics of preventing diabetes are complex. There is some evidence that diabetes prevention programmes are cost effective, but the evidence base to date provides few clear answers regarding design of prevention programmes because of differences in denominator populations, definitions, interventions and modelling assumptions.

Efficacy and effectiveness of screen and treat policies in prevention of type 2 diabetes: systematic review and meta-analysis of screening tests and interventions.

OBJECTIVES:  To assess diagnostic accuracy of screening tests for pre-diabetes and efficacy of interventions (lifestyle or metformin) in preventing onset of type 2 diabetes in people with pre-diabetes. DESIGN:  Systematic review and meta-analysis. DATA SOURCES AND METHOD:  Medline, PreMedline, and Embase. Study protocols and seminal papers were citation-tracked in Google Scholar to identify definitive trials and additional publications. Data on study design, methods, and findings were extracted onto Excel spreadsheets; a 20% sample was checked by a second researcher. Data extracted for screening tests included diagnostic accuracy and population prevalence. Two meta-analyses were performed, one summarising accuracy of screening tests (with the oral glucose tolerance test as the standard) for identification of pre-diabetes, and the other assessing relative risk of progression to type 2 diabetes after either lifestyle intervention or treatment with metformin. ELIGIBILITY CRITERIA:  Empirical studies evaluating accuracy of tests for identification of pre-diabetes. Interventions (randomised trials and interventional studies) with a control group in people identified through screening. No language restrictions. RESULTS:  2874 titles were scanned and 148 papers (covering 138 studies) reviewed in full. The final analysis included 49 studies of screening tests (five of which were prevalence studies) and 50 intervention trials. HbA1c had a mean sensitivity of 0.49 (95% confidence interval 0.40 to 0.58) and specificity of 0.79 (0.73 to 0.84), for identification of pre-diabetes, though different studies used different cut-off values. Fasting plasma glucose had a mean sensitivity of 0.25 (0.19 to 0.32) and specificity of 0.94 (0.92 to 0.96). Different measures of glycaemic abnormality identified different subpopulations (for example, 47% : of people with abnormal HbA1c had no other glycaemic abnormality). Lifestyle interventions were associated with a 36% (28% to 43%) reduction in relative risk of type 2 diabetes over six months to six years, attenuating to 20% (8% to 31%) at follow-up in the period after the trails. CONCLUSIONS:  HbA1c is neither sensitive nor specific for detecting pre-diabetes; fasting glucose is specific but not sensitive. Interventions in people classified through screening as having pre-diabetes have some efficacy in preventing or delaying onset of type 2 diabetes in trial populations. As screening is inaccurate, many people will receives an incorrect diagnosis and be referred on for interventions while others will be falsely reassured and not offered the intervention. These findings suggest that "screen and treat" policies alone are unlikely to have substantial impact on the worsening epidemic of type 2 diabetes. REGISTRATION:  PROSPERO (No CRD42016042920).

Ethnic group variations in alcohol-related hospital admissions in England: does place matter?

OBJECTIVES: The health burden of alcohol use is socially and geographically patterned in many countries. Less is known about variations in this burden between ethnic groups and whether this differs across place of residence. METHODS: National cross-sectional study using hospital admission data in England. Alcohol-related admission rates, where an alcohol-related condition was either the primary diagnosis (considered as the reason for admission) or a comorbidity, were calculated using ethnic group specific rates for English regions. RESULTS: In 2010/11 there were a total of 264,870 alcohol-related admissions in England. Admission rates were higher in the North of England than elsewhere (e.g. for primary diagnosis 161 per 100,000 population in the North vs. 62 per 100,000 in the South). These patterns were not uniform across ethnic groups however. For example, admission rates for alcohol-related comorbidity were four times higher among White Irish in London compared with those in the South of England (306 to 76 per 100,000) and four times higher in Indians living in the Midlands compared with those in the South of England (128 to 29 per 100,000). These patterns were similar for admissions with a comorbid alcohol-related condition. CONCLUSIONS: Geographical location may be an important determinant of within and between ethnic group variations in alcohol-related hospital admissions in England. While a number of factors were not examined here, this descriptive analysis suggests that this heterogeneity should be taken into account when planning interventions and services for the prevention and management of alcohol misuse.

Hyaluronidase gene profiling and role of hyal-1 overexpression in an orthotopic model of prostate cancer.

The mRNA levels of hyal-1, hyal-2, LUCA3 and PH20, the 4 hyaluronidases with demonstrated endoglucosaminidase activity, were extensively profiled in normal and tumor tissues and cell lines, using dot blot analysis and quantitative PCR. In normal tissues, hyal-1, hyal-2 and LUCA3 all showed unique patterns of mRNA expression, but were generally of widespread distribution, whereas PH20 mRNA was restricted to testes. In a small set of breast tumor samples, no elevations in hyal-1, hyal-2 or LUCA3 mRNA were seen. Hyaluronidase activity measured by a novel assay or zymography was also not elevated in sera from a number of breast cancer patients, compared to sera from normal volunteers. In ex vivo xenograft tumor cell lines, however, hyal-1 or hyal-2 mRNA levels were frequently elevated, whereas LUCA3 was only infrequently elevated and PH20 not at all. Two cell lines were engineered to overexpress hyal-1: a breast cancer line (CAL51) and a prostate cancer line (PC3M). Although the in vitro properties of the hyal-1 overexpressing cell lines were indistinguishable from the parental cells, the orthotopic growth of hyal-1 expressing PC3M cells in nu/nu mice resulted in significantly increased numbers of metastases, supportive of a role for hyal-1 in extravasation and metastatic tumor formation in this model of prostate cancer.