Postnatal Cardiometabolic Health After Metformin Use in Gestational Diabetes: A Secondary Analysis of the EMERGE Trial.

AIM: Women with GDM display adverse lifetime cardio-metabolic health. We examined whether early metformin in GDM could impact cardio-metabolic risk factors postpartum. RESEARCH DESIGN & METHODS: EMERGE, a double-blind, placebo-controlled trial randomized pregnancies 1:1 to placebo or metformin at GDM diagnosis and followed participants from randomization until 12±4 weeks postpartum. In total 478 pregnancies were available for postpartum maternal assessment, 237 and 241 assigned to metformin and placebo respectively. Weight (kg), body mass index (BMI) (kg/m2), waist circumference (cm) and blood pressure (mmHg) were measured, infant feeding method documented and bloods drawn for a 75 gram oral glucose tolerance test, fasting insulin, C peptide and lipid analysis. RESULTS: Despite similar weight and BMI at trial randomization, participants receiving metformin had significantly lower weight (79.5±15.9 vs 82.6±16.9kg; p=0.04) and BMI (29.3(5.6) vs 30.5(5.4); p=0.018) at the postpartum visit. However no difference in weight change from randomisation to 12 weeks postpartum was observed between metformin and placebo groups. Overall 29% (n=139) of the cohort met criteria for prediabetes or diabetes, with no positive impact with metformin. There were also no differences in measurements of insulin resistance, blood pressure or lipids between groups. CONCLUSION: Early metformin use in GDM did not impact important cardio-metabolic parameters in the early postpartum period despite significant benefits in weight gain and insulin use in pregnancy.

Prioritising Key Concepts for informed health choices in cancer: An evidence-based online educational programme.

Objective: The overabundance of health misinformation has undermined people's capacity to make evidence-based, informed choices about their health. Using the Informed Health Choices (IHC) Key Concepts (KCs), we are developing a two-stage education programme, Informed Health Choices-Cancer (IHC-C), to provide those impacted by cancer with the knowledge and skills necessary to think critically about the reliability of health information and claims and make well-informed choices. Stage 1 seeks to prioritise the most relevant Key Concepts. Methods: A project group and a patient and carer participation group completed a two-round prioritisation process. The process involved disseminating pre-reading materials, training sessions, and a structured judgement form to evaluate concepts for inclusion. Data from each round were analysed to reach a consensus on the concepts to include. Results: Fourteen participants were recruited and completed the first-round prioritisation. Fifteen participants undertook the second-round prioritisation. Nine Key Concepts were selected for the programme across five training sessions and two consensus meetings. Conclusion: The prioritised concepts identified represent the most pertinent aspects of cancer-related information for those impacted by the disease. By incorporating these concepts into educational materials and communication strategies, healthcare providers and organisations can potentially help cancer patients, survivors, and their loved ones to recognise and combat cancer-related misinformation more effectively. Innovation: This study introduces a participatory prioritisation process, which integrates the expertise of healthcare professionals with the insights of patients and carers, thereby enhancing the programme's relevance and applicability.

Consensus definition and diagnostic criteria for neonatal encephalopathy-study protocol for a real-time modified delphi study.

BACKGROUND: 'Neonatal encephalopathy' (NE) describes a group of conditions in term infants presenting in the earliest days after birth with disturbed neurological function of cerebral origin. NE is aetiologically heterogenous; one cause is peripartum hypoxic ischaemia. Lack of uniformity in the terminology used to describe NE and its diagnostic criteria creates difficulty in the design and interpretation of research and complicates communication with families. The DEFINE study aims to use a modified Delphi approach to form a consensus definition for NE, and diagnostic criteria. METHODS: Directed by an international steering group, we will conduct a systematic review of the literature to assess the terminology used in trials of NE, and with their guidance perform an online Real-time Delphi survey to develop a consensus diagnosis and criteria for NE. A consensus meeting will be held to agree on the final terminology and criteria, and the outcome disseminated widely. DISCUSSION: A clear and consistent consensus-based definition of NE and criteria for its diagnosis, achieved by use of a modified Delphi technique, will enable more comparability of research results and improved communication among professionals and with families. IMPACT: The terms Neonatal Encephalopathy and Hypoxic Ischaemic Encephalopathy tend to be used interchangeably in the literature to describe a term newborn with signs of encephalopathy at birth. This creates difficulty in communication with families and carers, and between medical professionals and researchers, as well as creating difficulty with performance of research. The DEFINE project will use a Real-time Delphi approach to create a consensus definition for the term 'Neonatal Encephalopathy'. A definition formed by this consensus approach will be accepted and utilised by the neonatal community to improve research, outcomes, and parental experience.

Outcomes of interventions in neonatal sepsis: A systematic review of qualitative research.

BACKGROUND: While a systematic review exists detailing neonatal sepsis outcomes from clinical trials, there remains an absence of a qualitative systematic review capturing the perspectives of key stakeholders. OBJECTIVES: Our aim is to identify outcomes from qualitative research on any intervention to prevent or improve the outcomes of neonatal sepsis that are important to parents, other family members, healthcare providers, policymakers, and researchers as a part of the development of a core outcome set (COS) for neonatal sepsis. SEARCH STRATEGY: A literature search was carried out using MEDLINE, EMBASE, CINAHL, and PsycInfo databases. SELECTION CRITERIA: Publications describing qualitative data relating to neonatal sepsis outcomes were included. DATA COLLECTION AND ANALYSIS: Drawing on the concepts of thematic synthesis, texts related to outcomes were coded and grouped. These outcomes were then mapped to the domain headings of an existing model. MAIN RESULTS: Out of 6777 records screened, six studies were included. Overall, 19 outcomes were extracted from the included studies. The most frequently reported outcomes were those in the domains related to parents, healthcare workers and individual organ systemas such as gastrointestinal system. The remaining outcomes were classified under the headings of general outcomes, miscellaneous outcomes, survival, and infection. CONCLUSIONS: The outcomes identified in this review are different from those reported in neonatal sepsis clinical trials, thus highlighting the importance of incorporating qualitative studies into COS development to encapsulate all relevant stakeholders' perspectives.

Surgical Handover Core Outcome Measures (SH-CORE): a protocol for the development of a core outcome set for trials in surgical handover.

BACKGROUND: Surgical handover is associated with a significant risk of care failures. Existing research displays methodological deficiencies and little consensus on the outcomes that should be used to evaluate interventions in this area. This paper reports a protocol to develop a core outcome set (COS) to support standardisation, comparability, and evidence synthesis in future studies of surgical handover between doctors. METHODS: This study adheres to the Core Outcome Measures in Effectiveness Trials (COMET) initiative guidance for COS development, including the COS-Standards for Development (COS-STAD) and Reporting (COS-STAR) recommendations. It has been registered prospectively on the COMET database and will be led by an international steering group that includes surgical healthcare professionals, researchers, and patient and public partners. An initial list of reported outcomes was generated through a systematic review of interventions to improve surgical handover (PROSPERO: CRD42022363198). Findings of a qualitative evidence synthesis of patient and public perspectives on handover will augment this list, followed by a real-time Delphi survey involving all stakeholder groups. Each Delphi participant will then be invited to take part in at least one online consensus meeting to finalise the COS. ETHICS AND DISSEMINATION: This study was approved by the Royal College of Surgeons in Ireland (RCSI) Research Ethics Committee (202309015, 7th November 2023). Results will be presented at surgical scientific meetings and submitted to a peer-reviewed journal. A plain English summary will be disseminated through national websites and social media. The authors aim to integrate the COS into the handover curriculum of the Irish national surgical training body and ensure it is shared internationally with other postgraduate surgical training programmes. Collaborators will be encouraged to share the findings with relevant national health service functions and national bodies. DISCUSSION: This study will represent the first published COS for interventions to improve surgical handover, the first use of a real-time Delphi survey in a surgical context, and will support the generation of better-quality evidence to inform best practice. TRIAL REGISTRATION: Core Outcome Measures in Effectiveness Trials (COMET) initiative 2675.  http://www.comet-initiative.org/Studies/Details/2675 .

Midwife continuity of care models versus other models of care for childbearing women.

BACKGROUND: Midwives are primary providers of care for childbearing women globally and there is a need to establish whether there are differences in effectiveness between midwife continuity of care models and other models of care. This is an update of a review published in 2016. OBJECTIVES: To compare the effects of midwife continuity of care models with other models of care for childbearing women and their infants. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Trials Register, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP) (17 August 2022), as well as the reference lists of retrieved studies. SELECTION CRITERIA: All published and unpublished trials in which pregnant women are randomly allocated to midwife continuity of care models or other models of care during pregnancy and birth. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for inclusion criteria, scientific integrity, and risk of bias, and carried out data extraction and entry. Primary outcomes were spontaneous vaginal birth, caesarean section, regional anaesthesia, intact perineum, fetal loss after 24 weeks gestation, preterm birth, and neonatal death. We used GRADE to rate the certainty of evidence. MAIN RESULTS: We included 17 studies involving 18,533 randomised women. We assessed all studies as being at low risk of scientific integrity/trustworthiness concerns. Studies were conducted in Australia, Canada, China, Ireland, and the United Kingdom. The majority of the included studies did not include women at high risk of complications. There are three ongoing studies targeting disadvantaged women. Primary outcomes Based on control group risks observed in the studies, midwife continuity of care models, as compared to other models of care, likely increase spontaneous vaginal birth from 66% to 70% (risk ratio (RR) 1.05, 95% confidence interval (CI) 1.03 to 1.07; 15 studies, 17,864 participants; moderate-certainty evidence), likelyreduce caesarean sections from 16% to 15% (RR 0.91, 95% CI 0.84 to 0.99; 16 studies, 18,037 participants; moderate-certainty evidence), and likely result in little to no difference in intact perineum (29% in other care models and 31% in midwife continuity of care models, average RR 1.05, 95% CI 0.98 to 1.12; 12 studies, 14,268 participants; moderate-certainty evidence). There may belittle or no difference in preterm birth (< 37 weeks) (6% under both care models, average RR 0.95, 95% CI 0.78 to 1.16; 10 studies, 13,850 participants; low-certainty evidence). We arevery uncertain about the effect of midwife continuity of care models on regional analgesia (average RR 0.85, 95% CI 0.79 to 0.92; 15 studies, 17,754 participants, very low-certainty evidence), fetal loss at or after 24 weeks gestation (average RR 1.24, 95% CI 0.73 to 2.13; 12 studies, 16,122 participants; very low-certainty evidence), and neonatal death (average RR 0.85, 95% CI 0.43 to 1.71; 10 studies, 14,718 participants; very low-certainty evidence). Secondary outcomes When compared to other models of care, midwife continuity of care models likely reduce instrumental vaginal birth (forceps/vacuum) from 14% to 13% (average RR 0.89, 95% CI 0.83 to 0.96; 14 studies, 17,769 participants; moderate-certainty evidence), and may reduceepisiotomy 23% to 19% (average RR 0.83, 95% CI 0.77 to 0.91; 15 studies, 17,839 participants; low-certainty evidence). When compared to other models of care, midwife continuity of care models likelyresult in little to no difference inpostpartum haemorrhage (average RR 0.92, 95% CI 0.82 to 1.03; 11 studies, 14,407 participants; moderate-certainty evidence) and admission to special care nursery/neonatal intensive care unit (average RR 0.89, 95% CI 0.77 to 1.03; 13 studies, 16,260 participants; moderate-certainty evidence). There may be little or no difference in induction of labour (average RR 0.92, 95% CI 0.85 to 1.00; 14 studies, 17,666 participants; low-certainty evidence), breastfeeding initiation (average RR 1.06, 95% CI 1.00 to 1.12; 8 studies, 8575 participants; low-certainty evidence), and birth weight less than 2500 g (average RR 0.92, 95% CI 0.79 to 1.08; 9 studies, 12,420 participants; low-certainty evidence). We are very uncertain about the effect of midwife continuity of care models compared to other models of care onthird or fourth-degree tear (average RR 1.10, 95% CI 0.81 to 1.49; 7 studies, 9437 participants; very low-certainty evidence), maternal readmission within 28 days (average RR 1.52, 95% CI 0.78 to 2.96; 1 study, 1195 participants; very low-certainty evidence), attendance at birth by a known midwife (average RR 9.13, 95% CI 5.87 to 14.21; 11 studies, 9273 participants; very low-certainty evidence), Apgar score less than or equal to seven at five minutes (average RR 0.95, 95% CI 0.72 to 1.24; 13 studies, 12,806 participants; very low-certainty evidence) andfetal loss before 24 weeks gestation (average RR 0.82, 95% CI 0.67 to 1.01; 12 studies, 15,913 participants; very low-certainty evidence). No maternal deaths were reported across three studies. Although the observed risk of adverse events was similar between midwifery continuity of care models and other models, our confidence in the findings was limited. Our confidence in the findings was lowered by possible risks of bias, inconsistency, and imprecision of some estimates. There were no available data for the outcomes: maternal health status, neonatal readmission within 28 days, infant health status, and birth weight of 4000 g or more. Maternal experiences and cost implications are described narratively. Women receiving care from midwife continuity of care models, as opposed to other care models, generally reported more positive experiences during pregnancy, labour, and postpartum. Cost savings were noted in the antenatal and intrapartum periods in midwife continuity of care models. AUTHORS' CONCLUSIONS: Women receiving midwife continuity of care models were less likely to experience a caesarean section and instrumental birth, and may be less likely to experience episiotomy. They were more likely to experience spontaneous vaginal birth and report a positive experience. The certainty of some findings varies due to possible risks of bias, inconsistencies, and imprecision of some estimates. Future research should focus on the impact on women with social risk factors, and those at higher risk of complications, and implementation and scaling up of midwife continuity of care models, with emphasis on low- and middle-income countries.

Co-design workshops to develop evidence synthesis summary formats for use by clinical guideline development groups.

BACKGROUND: Evidence synthesis is used by decision-makers in various ways, such as developing evidence-based recommendations for clinical guidelines. Clinical guideline development groups (GDGs) typically discuss evidence synthesis findings in a multidisciplinary group, including patients, healthcare providers, policymakers, etc. A recent mixed methods systematic review (MMSR) identified no gold standard format for optimally presenting evidence synthesis findings to these groups. However, it provided 94 recommendations to help produce more effective summary formats for general evidence syntheses (e.g., systematic reviews). To refine the MMSR recommendations to create more actionable guidance for summary producers, we aimed to explore these 94 recommendations with participants involved in evidence synthesis and guideline development. METHODS: We conducted a descriptive qualitative study using online focus group workshops in February and March 2023. These groups used a participatory co-design approach with interactive voting activities to identify preferences for a summary format's essential content and style. We created a topic guide focused on recommendations from the MMSR with mixed methods support, ≥ 3 supporting studies, and those prioritized by an expert advisory group via a pragmatic prioritization exercise using the MoSCoW method (Must, Should, Could, and Will not haves). Eligible participants must be/have been involved in GDGs and/or evidence synthesis. Groups were recorded and transcribed. Two independent researchers analyzed transcripts using directed content analysis with 94 pre-defined codes from the MMSR. RESULTS: Thirty individuals participated in six focus groups. We coded 79 of the 94 pre-defined codes. Participants suggested a "less is more" structured approach that minimizes methodological steps and statistical data, promoting accessibility to all audiences by judicious use of links to further information in the full report. They emphasized concise, consistently presented formats that highlight key messages, flag readers to indicators of trust in the producers (i.e., logos, websites, and conflict of interest statements), and highlight the certainty of evidence (without extenuating details). CONCLUSIONS: This study identified guidance based on the preferences of guideline developers and evidence synthesis producers about the format of evidence synthesis summaries to support decision-making. The next steps involve developing and user-testing prototype formats through one-on-one semi-structured interviews to optimize evidence synthesis summaries and support decision-making.

Rapid reviews methods series: assessing the appropriateness of conducting a rapid review.

This paper, part of the Cochrane Rapid Review Methods Group series, offers guidance on determining when to conduct a rapid review (RR) instead of a full systematic review (SR). While both review types aim to comprehensively synthesise evidence, RRs, conducted within a shorter time frame of typically 6 months or less, involve streamlined methods to expedite the process. The decision to opt for an RR depends on the urgency of the research question, resource availability and the impact on decision outcomes. The paper categorises scenarios where RRs are appropriate, including urgent decision-making, informing guidelines, assessing new technologies and identifying evidence gaps. It also outlines instances when RRs may be inappropriate, cautioning against conducting them solely for ease, quick publication or only cost-saving motives.When deciding on an RR, it is crucial to consider both conceptual and practical factors. These factors encompass the urgency of needing timely evidence, the consequences of waiting for a full SR, the potential risks associated with incomplete evidence, and the risk of not using synthesised evidence in decision-making, among other considerations. Key factors to weigh also include having a clearly defined need, a manageable scope and access to the necessary expertise. Overall, this paper aims to guide informed judgements about whether to choose an RR over an SR based on the specific research question and context. Researchers and decision-makers are encouraged to carefully weigh potential trade-offs when opting for RRs.

Undertaking Studies Within A Trial to evaluate recruitment and retention strategies for randomised controlled trials: lessons learnt from the PROMETHEUS research programme.

Background: Randomised controlled trials ('trials') are susceptible to poor participant recruitment and retention. Studies Within A Trial are the strongest methods for testing the effectiveness of strategies to improve recruitment and retention. However, relatively few of these have been conducted. Objectives: PROMoting THE Use of Studies Within A Trial aimed to facilitate at least 25 Studies Within A Trial evaluating recruitment or retention strategies. We share our experience of delivering the PROMoting THE Use of Studies Within A Trial programme, and the lessons learnt for undertaking randomised Studies Within A Trial. Design: A network of 10 Clinical Trials Units and 1 primary care research centre committed to conducting randomised controlled Studies Within A Trial of recruitment and/or retention strategies was established. Promising recruitment and retention strategies were identified from various sources including Cochrane systematic reviews, the Study Within A Trial Repository, and existing prioritisation exercises, which were reviewed by patient and public members to create an initial priority list of seven recruitment and eight retention interventions. Host trial teams could apply for funding and receive support from the PROMoting THE Use of Studies Within A Trial team to undertake Studies Within A Trial. We also tested the feasibility of undertaking co-ordinated Studies Within A Trial, across multiple host trials simultaneously. Setting: Clinical trials unit-based trials recruiting or following up participants in any setting in the United Kingdom were eligible. Participants: Clinical trials unit-based teams undertaking trials in any clinical context in the United Kingdom. Interventions: Funding of up to £5000 and support from the PROMoting THE Use of Studies Within A Trial team to design, implement and report Studies Within A Trial. Main outcome measures: Number of host trials funded. Results: Forty-two Studies Within A Trial were funded (31 host trials), across 12 Clinical Trials Units. The mean cost of a Study Within A Trial was £3535. Twelve Studies Within A Trial tested the same strategy across multiple host trials using a co-ordinated Study Within A Trial design, and four used a factorial design. Two recruitment and five retention strategies were evaluated in more than one host trial. PROMoting THE Use of Studies Within A Trial will add 18% more Studies Within A Trial to the Cochrane systematic review of recruitment strategies, and 79% more Studies Within A Trial to the Cochrane review of retention strategies. For retention, we found that pre-notifying participants by card, letter or e-mail before sending questionnaires was effective, as was the use of pens, and sending personalised text messages to improve questionnaire response. We highlight key lessons learnt to guide others planning Studies Within A Trial, including involving patient and public involvement partners; prioritising and selecting strategies to evaluate and elements to consider when designing a Study Within A Trial; obtaining governance approvals; implementing Studies Within A Trial, including individual and co-ordinated Studies Within A Trials; and reporting Study Within A Trials. Limitations: The COVID-19 pandemic negatively impacted five Studies Within A Trial, being either delayed (n = 2) or prematurely terminated (n = 3). Conclusions: PROMoting THE Use of Studies Within A Trial significantly increased the evidence base for recruitment and retention strategies. When provided with both funding and practical support, host trial teams successfully implemented Studies Within A Trial. Future work: Future research should identify and target gaps in the evidence base, including widening Study Within A Trial uptake, undertaking more complex Studies Within A Trial and translating Study Within A Trial evidence into practice. Study registration: All Studies Within A Trial in the PROMoting THE Use of Studies Within A Trial programme had to be registered with the Northern Ireland Network for Trials Methodology Research Study Within A Trial Repository. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/55/80) and is published in full in Health Technology Assessment; Vol. 28, No. 2. See the NIHR Funding and Awards website for further award information.

A Study Within A Trial is a research study nested inside a larger 'host trial', promoting the use of Studies Within A Trial aimed to do Study Within A Trial routine practice in clinical trial units by funding and supporting at least 25 Studies Within A Trial. The best way to test health and social care treatments is to do a randomised controlled trial ('trial'), where some patients get the treatment being tested and some do not. The results of different groups are compared to see if the treatment improves care. Recruiting patients and keeping them involved in trials is often very difficult. Research teams often do not know how best to recruit and keep patients engaged as the methods have not been tested to see if they work. The best way to test these methods is by doing a Study Within A Trial. We test a programme of Studies Within A Trial for recruiting and keeping patients engaged in trials. Trial teams were able to apply for funding of up to £5000 and receive support from Promoting the use of Study Within A Trial team to do Studies Within A Trial. We used our experience of doing Studies Within A Trial to outline lessons learnt for doing Studies Within A Trial. We funded 42 Studies Within A Trial and gave teams necessary advice to do them. We significantly increased the knowledge for both recruitment and retention strategies, and found 'pre-notifying' before sending questionnaires, sending pens and personalised text messages were all effective for increasing responses by participants. We tested Studies Within A Trial across several different trials at the same time to find out more quickly whether their methods worked. We highlight key lessons learnt to guide others doing Studies Within A Trial, including involving patient partners; picking the right strategy to test; getting ethical approvals; how to do and report Studies Within A Trial. Promoting the use of studies within a trial was successful and supported more Studies Within A Trial than planned. We hope our experience will support those doing Studies Within A Trial in the future.

Rapid reviews methods series: Guidance on assessing the certainty of evidence.

This paper is part of a series of methodological guidance from the Cochrane Rapid Reviews Methods Group. Rapid reviews (RRs) use modified systematic review methods to accelerate the review process while maintaining systematic, transparent and reproducible methods. This paper addresses considerations for rating the certainty of evidence (COE) in RRs. We recommend the full implementation of GRADE (Grading of Recommendations, Assessment, Development and Evaluation) for Cochrane RRs if time and resources allow.If time or other resources do not permit the full implementation of GRADE, the following recommendations can be considered: (1) limit rating COE to the main intervention and comparator and limit the number of outcomes to critical benefits and harms; (2) if a literature review or a Delphi approach to rate the importance of outcomes is not feasible, rely on informal judgements of knowledge users, topic experts or team members; (3) replace independent rating of the COE by two reviewers with single-reviewer rating and verification by a second reviewer and (4) if effect estimates of a well-conducted systematic review are incorporated into an RR, use existing COE grades from such a review. We advise against changing the definition of COE or the domains considered part of the GRADE approach for RRs.

COHESION: a core outcome set for the treatment of neonatal encephalopathy.

BACKGROUND: Heterogeneity in outcomes reported in trials of interventions for the treatment of neonatal encephalopathy (NE) makes evaluating the effectiveness of treatments difficult. Developing a core outcome set for NE treatment would enable researchers to measure and report the same outcomes in future trials. This would minimise waste, ensure relevant outcomes are measured and enable evidence synthesis. Therefore, we aimed to develop a core outcome set for treating NE. METHODS: Outcomes identified from a systematic review of the literature and interviews with parents were prioritised by stakeholders (n = 99 parents/caregivers, n = 101 healthcare providers, and n = 22 researchers/ academics) in online Delphi surveys. Agreement on the outcomes was achieved at online consensus meetings attended by n = 10 parents, n = 18 healthcare providers, and n = 13 researchers/ academics. RESULTS: Seven outcomes were included in the final core outcome set: survival; brain injury on imaging; neurological status at discharge; cerebral palsy; general cognitive ability; quality of life of the child, and adverse events related to treatment. CONCLUSION: We developed a core outcome set for the treatment of NE. This will allow future trials to measure and report the same outcomes and ensure results can be compared. Future work should identify how best to measure the COS. IMPACT: We have identified seven outcomes that should be measured and reported in all studies for the treatment of neonatal encephalopathy. Previously, a core outcome set for neonatal encephalopathy treatments did not exist. This will help to reduce heterogeneity in outcomes reported in clinical trials and other studies, and help researchers identify the best treatments for neonatal encephalopathy.

Protocol for the development of a core outcome set for neonatal sepsis (NESCOS).

Neonatal sepsis is a serious public health problem; however, there is substantial heterogeneity in the outcomes measured and reported in research evaluating the effectiveness of the treatments. Therefore, we aim to develop a Core Outcome Set (COS) for studies evaluating the effectiveness of treatments for neonatal sepsis. Since a systematic review of key outcomes from randomised trials of therapeutic interventions in neonatal sepsis was published recently, we will complement this with a qualitative systematic review of the key outcomes of neonatal sepsis identified by parents, other family members, parent representatives, healthcare providers, policymakers, and researchers. We will interpret the outcomes of both studies using a previously established framework. Stakeholders across three different groups i.e., (1) researchers, (2) healthcare providers, and (3) patients' parents/family members and parent representatives will rate the importance of the outcomes in an online Real-Time Delphi Survey. Afterwards, consensus meetings will be held to agree on the final COS through online discussions with key stakeholders. This COS is expected to minimize outcome heterogeneity in measurements and publications, improve comparability and synthesis, and decrease research waste.

Early Metformin in Gestational Diabetes: A Randomized Clinical Trial.

Importance: Gestational diabetes is a common complication of pregnancy and the optimal management is uncertain. Objective: To test whether early initiation of metformin reduces insulin initiation or improves fasting hyperglycemia at gestation weeks 32 or 38. Design, Setting, and Participants: Double-blind, placebo-controlled trial conducted in 2 centers in Ireland (one tertiary hospital and one smaller regional hospital). Participants were enrolled from June 2017 through September 2022 and followed up until 12 weeks' postpartum. Participants comprised 510 individuals (535 pregnancies) diagnosed with gestational diabetes based on World Health Organization 2013 criteria. Interventions: Randomized 1:1 to either placebo or metformin (maximum dose, 2500 mg) in addition to usual care. Main Outcomes And Measures: The primary outcome was a composite of insulin initiation or a fasting glucose level of 5.1 mmol/L or greater at gestation weeks 32 or 38. Results: Among 510 participants (mean age, 34.3 years), 535 pregnancies were randomized. The primary composite outcome was not significantly different between groups and occurred in 150 pregnancies (56.8%) in the metformin group and 167 pregnancies (63.7%) in the placebo group (between-group difference, -6.9% [95% CI, -15.1% to 1.4%]; relative risk, 0.89 [95% CI, 0.78-1.02]; P = .13). Of 6 prespecified secondary maternal outcomes, 3 favored the metformin group, including time to insulin initiation, self-reported capillary glycemic control, and gestational weight gain. Secondary neonatal outcomes differed by group, with smaller neonates (lower mean birth weights, a lower proportion weighing >4 kg, a lower proportion in the >90% percentile, and smaller crown-heel length) in the metformin group without differences in neonatal intensive care needs, respiratory distress requiring respiratory support, jaundice requiring phototherapy, major congenital anomalies, neonatal hypoglycemia, or proportion with 5-minute Apgar scores less than 7. Conclusion and relevance: Early treatment with metformin was not superior to placebo for the composite primary outcome. Prespecified secondary outcome data support further investigation of metformin in larger clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02980276; EudraCT: 2016-001644-19.

A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials.

Background: Interventional trials that evaluate treatment effects using surrogate endpoints have become increasingly common. This paper describes four linked empirical studies and the development of a framework for defining, interpreting and reporting surrogate endpoints in trials. Methods: As part of developing the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) extensions for randomised trials reporting surrogate endpoints, we undertook a scoping review, e-Delphi study, consensus meeting, and a web survey to examine current definitions and stakeholder (including clinicians, trial investigators, patients and public partners, journal editors, and health technology experts) interpretations of surrogate endpoints as primary outcome measures in trials. Findings: Current surrogate endpoint definitional frameworks are inconsistent and unclear. Surrogate endpoints are used in trials as a substitute of the treatment effects of an intervention on the target outcome(s) of ultimate interest, events measuring how patients feel, function, or survive. Traditionally the consideration of surrogate endpoints in trials has focused on biomarkers (e.g., HDL cholesterol, blood pressure, tumour response), especially in the medical product regulatory setting. Nevertheless, the concept of surrogacy in trials is potentially broader. Intermediate outcomes that include a measure of function or symptoms (e.g., angina frequency, exercise tolerance) can also be used as substitute for target outcomes (e.g., all-cause mortality)-thereby acting as surrogate endpoints. However, we found a lack of consensus among stakeholders on accepting and interpreting intermediate outcomes in trials as surrogate endpoints or target outcomes. In our assessment, patients and health technology assessment experts appeared more likely to consider intermediate outcomes to be surrogate endpoints than clinicians and regulators. Interpretation: There is an urgent need for better understanding and reporting on the use of surrogate endpoints, especially in the setting of interventional trials. We provide a framework for the definition of surrogate endpoints (biomarkers and intermediate outcomes) and target outcomes in trials to improve future reporting and aid stakeholders' interpretation and use of trial surrogate endpoint evidence. Funding: SPIRIT-SURROGATE/CONSORT-SURROGATE project is Medical Research Council Better Research Better Health (MR/V038400/1) funded.