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Abstract Background The field of digital mental health has followed an exponential growth trajectory in recent years. While the evidence base has increased significantly, its adoption within health and care services has been slowed by several challenges, including a lack of knowledge from researchers regarding how to navigate the pathway for mandatory regulatory approval. This paper details the steps that a team must take to achieve the required approvals to carry out a research study using a novel digital mental health intervention. We used a randomised controlled trial of a digital mental health intervention called STOP (Successful Treatment of Paranoia) as a worked example. Methods The methods section explains the two main objectives that are required to achieve regulatory approval (MHRA Notification of No Objection) and the detailed steps involved within each, as carried out for the STOP trial. First, the existing safety of digital mental health interventions must be demonstrated. This can refer to literature reviews, any feasibility/pilot safety data, and requires a risk management plan. Second, a detailed plan to further evaluate the safety of the digital mental health intervention is needed. As part of this we describe the STOP study’s development of a framework for categorising adverse events and based on this framework, a tool to collect adverse event data. Results We present literature review results, safety-related feasibility study findings and the full risk management plan for STOP, which addressed 26 possible hazards, and included the 6-point scales developed to quantify the probability and severity of typical risks involved when a psychiatric population receives a digital intervention without the direct support of a therapist. We also present an Adverse Event Category Framework for Digital Therapeutic Devices and the Adverse Events Checklist—which assesses 15 different categories of adverse events—that was constructed from this and used in the STOP trial. Conclusions The example shared in this paper serves as a guide for academics and professionals working in the field of digital mental health. It provides insights into the safety assessment requirements of regulatory bodies when a clinical investigation of a digital mental health intervention is proposed. Methods, scales and tools that could easily be adapted for use in other similar research are presented, with the expectation that these will assist other researchers in the field seeking regulatory approval for digital mental health products.

Abstract Background Clinicians and researchers should consider the expected benefits and potential harms of an intervention. Parenting programmes are a widely used evidence-based intervention for child behaviour problems. However, few data are available on potential negative effects. The aims of this paper were to increase systematic knowledge of adverse event (AE) assessment in parenting programmes and to provide an AE assessment tool. Methods As part of the RISE project (prevention of child mental health problems in South-eastern Europe—adapt, optimise, test and extend parenting for lifelong health), we developed and tested an AE assessment procedure in three sequential studies for parents of children with child behaviour problems aged 2 to 9 years in North Macedonia, Republic of Moldova, and Romania. This paper reports on the development of the assessment tool in phase 1 (N = 140), phase 2 (N = 835), and the final experiences with using the optimised procedures in phase 3 (multisite randomised controlled trial, N = 823) in which AEs were assessed before, three times during intervention delivery, and at 1 year follow-up. At each time point, the participants completed a 12-item AE checklist. If moderate-to-severe problems of parent or child were reported, a structured follow-up interview was conducted. Results The response rate on the AE assessment tool increased from 6% (phase 1) to 100% (phase 3) indicating improvement in collecting these data based on the experiences of each phase. Results of the RCT (phase 3) showed generally low (S)AE frequencies with the finally optimised procedure: During the intervention, no serious adverse events (SAE) were registered; at least one AE was reported by 10% (after the first session), 7% (after the third session), and 4% (after the last fifth session) of participants. None of the identified (S)AEs was causally related to the study or intervention. Cost–benefit considerations are needed to determine the best way to ensure participant safety in parenting programmes. Conclusion The applied active AE assessment procedure provides a comprehensive AE assessment tool that can be used by others—with adaptations for the specific context, if needed. Based on our experiences, we outline recommendations for future studies. Trial registration ClinicalTrials.gov, registration number phase 1: NCT03552250; phase 2: NCT03865485, phase 3: NCT04721730 . Registered on 13 January 2021.

Abstract Background The SAVVY project aims to improve the analyses of adverse events (AEs) in clinical trials through the use of survival techniques appropriately dealing with varying follow-up times and competing events (CEs). This paper summarizes key features and conclusions from the various SAVVY papers. Methods Summarizing several papers reporting theoretical investigations using simulations and an empirical study including randomized clinical trials from several sponsor organizations, biases from ignoring varying follow-up times or CEs are investigated. The bias of commonly used estimators of the absolute (incidence proportion and one minus Kaplan-Meier) and relative (risk and hazard ratio) AE risk is quantified. Furthermore, we provide a cursory assessment of how pertinent guidelines for the analysis of safety data deal with the features of varying follow-up time and CEs. Results SAVVY finds that for both, avoiding bias and categorization of evidence with respect to treatment effect on AE risk into categories, the choice of the estimator is key and more important than features of the underlying data such as percentage of censoring, CEs, amount of follow-up, or value of the gold-standard. Conclusions The choice of the estimator of the cumulative AE probability and the definition of CEs are crucial. Whenever varying follow-up times and/or CEs are present in the assessment of AEs, SAVVY recommends using the Aalen-Johansen estimator (AJE) with an appropriate definition of CEs to quantify AE risk. There is an urgent need to improve pertinent clinical trial reporting guidelines for reporting AEs so that incidence proportions or one minus Kaplan-Meier estimators are finally replaced by the AJE with appropriate definition of CEs.

Background There is a policy drive in NHS maternity services to improve open disclosure with harmed families and limited information on how better practice can be achieved. Objectives To identify critical factors for improving open disclosure from the perspectives of families, doctors, midwives and services and to produce actionable evidence for service improvement. Design A three-phased, qualitative study using realist methodology. Phase 1: two literature reviews: scoping review of post-2013 NHS policy and realist synthesis of initial programme theories for improvement; an interview study with national stakeholders in NHS maternity safety and families. Phase 2: in-depth ethnographic case studies within three NHS maternity services in England. Phase 3: interpretive forums with study participants. A patient and public involvement strategy underpinned all study phases. Setting National recruitment (study phases 1 and 3); three English maternity services (study phase 2). Participants We completed n = 142 interviews, including 27 with families; 93 hours of ethnographic observations, including 52 service and family meetings over 9 months; and interpretive forums with approximately 69 people, including 11 families. Results The policy review identified a shift from viewing injured families as passive recipients to active contributors of post-incident learning, but a lack of actionable guidance for improving family involvement. The realist synthesis found weak evidence of the effectiveness of open disclosure interventions in the international maternity literature, but some improvements with organisation-wide interventions. Recent evidence was predominantly from the United Kingdom. The research identified and explored five key mechanisms for open disclosure: meaningful acknowledgement of harm; involvement of those affected in reviews/investigations; support for families’ own sense-making; psychological safely of skilled clinicians (doctors and midwives); and knowing that improvements to care have happened. The need for each family to make sense of the incident in their own terms is noted. The selective initiatives of some clinicians to be more open with some families is identified. The challenges of an adversarial medicolegal landscape and limited support for meeting incentivised targets is evidenced. Limitations Research was conducted after the pandemic, with exceptional pressure on services. Case-study ethnography was of three higher performing services: generalisation from case-study findings is limited. No observations of Health Safety Investigation Branch investigations were possible without researcher access. Family recruitment did not reflect population diversity with limited representation of non-white families, families with disabilities and other socially marginalised groups and disadvantaged groups. Conclusions We identify the need for service-wide systems to ensure that injured families are positioned at the centre of post-incident events, ensure appropriate training and post-incident care of clinicians, and foster ongoing engagement with families beyond the individual efforts made by some clinicians for some families. The need for legislative revisions to promote openness with families across NHS organisations, and wider changes in organisational family engagement practices, is indicated. Examination of how far the study’s findings apply to different English maternity services, and a wider rethinking of how family diversity can be encouraged in maternity services research. Study registration This study is registered as PROSPERO CRD42020164061. The study has been assessed following RAMESES realist guidelines. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research Programme (NIHR award ref: 17/99/85) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 22. See the NIHR Funding and Awards website for further award information. Plain language summary This study describes the experiences of families and healthcare professionals involved in incidents in NHS maternity care. The incidents caused harm-like injury or death to the baby or woman. We wanted to know whether services involved families in investigations and reviews and how this was done, what worked well, what did not work well and why. To do this, we first looked at what had already been written about ‘open disclosure’ or OD. Open disclosure is when the NHS admits to families that the care they provided has directly caused harm. After open disclosure occurs, families should be involved in making sure that the NHS learns so it can deliver better care for families in the future. In our reading, we found that families want a meaningful apology, to be involved in reviews or investigations, to know what happened to their loved one, to be cared for by knowledgeable doctors and midwives who are supported in providing open disclosure and to know things have changed because of what happened. Recommendations for involving families in open disclosure have improved, but there is still work to be done to make sure families are involved. Next, we talked to over 100 healthcare professionals involved in government policy for open disclosure in maternity services and 27 families who experienced harm. We spent 9 months observing the work of clinicians at three maternity services to watch open disclosure. We shared early findings with families, doctors, midwives and managers, and included their views. We found that services need to provide dedicated time, education and emotional support for staff who provide open disclosure. Services need to ensure that families have ongoing support and better communication about incidents. Finally, families must be involved in the review process if they want to be with their experiences reflected in reports and kept informed of ongoing improvements. Scientific summary Background A range of interventions have been introduced in the UK NHS to improve post-incident communication and support of injured families. However, there is limited evidence on the progress of this work and how improvements in open disclosure (OD) are to be embedded. Study aims and objectives The aim was to identify the critical, underlying factors for improving the incidence and quality of post-incident communication with families in NHS maternity services. This required examination of what is necessary and required in different contexts for OD processes and practices to be strengthened for families, doctors and midwives (henceforth clinicians) and service managers. Following a realist evaluation approach, the study objectives were to: establish initial hypotheses to focus investigation of OD improvements in NHS maternity services in England examine the scope of OD in NHS maternity services from the perspectives of regional and national stakeholders refine our initial hypotheses in relation to the analysis of regional and national stakeholder perspectives conduct an in-depth study of OD improvement within services verify data interpretation and study output development with different stakeholders (families, clinicians, service managers and national policy-makers). Overview of methods A qualitative study using realist evaluation methodology to evaluate the progress of OD in English NHS maternity services was conducted (May 2019–March 2022) in three sequential study phases (SPs). Realist approaches are theory-driven and designed for investigation of complex social interventions. They consider if and how an intervention works in different circumstances from the perspectives of different people. Initial hypotheses, developed from the use of a realist evaluation conceptual tool [context–mechanism–outcome (C–M–O) configurations], are developed from literature synthesis and ‘tested’ by primary research to identify potential causal relationships that explain how an intervention works. A Project Advisory Group (PAG), including families, participated in study decisions, from initial theory development, case-study sampling, data collection and interpretation of study findings against a background of rapid policy change. Primary data collection was from November 2019 to January 2022. A patient involvement and public engagement strategy sought to maximise family involvement in all stages of the study cycle. Study phase1a: literature review A scoping review examined recent (2014–22) policy recommendations for family engagement improvements in NHS maternity services. Documents were identified through database searching and included if they were related to safety, incidents, harm, reviews and investigations in maternity care. Academic papers; essays; conference abstractions, papers and presentations; and research studies were excluded. The realist synthesis of primary evidence of the progress of interventions for strengthening OD in international maternity settings included 38 documents appraised for relevance and rigour. Documents were from key database searches, included all English language sources (post 2000), without predetermined exclusion criteria for research methods. Only primary research evidence or evidence synthesis was included. Programme theories were developed with our PAG for testing during later SPs. Study phase 1b: national and regional stakeholder interview study National and regional stakeholders (n = 44), and families (n = 23), were interviewed following a topic guide developed from our literature synthesis. Families included in the study have histories of significant injury, including the stillbirth, death or serious injury of their baby and/or themselves (dating from 2007 to 2021). Study phase 2: ethnographic case studies Three maternity services in two Trusts were identified for in-depth ethnographic research by purposive sampling, based on their capacity to accommodate research immediately following the coronavirus disease 2019 (COVID-19) pandemic, and evidence of their positive deviance in improvement work on openness identified from public data sets. Across these services, we conducted: staff interviews (n = 75) and three return staff interviews, family interviews (n = 4), observations of staff and family meetings (n = 52) and observations of informal unit and office activities (all observations totalled 93 hours, with 30 hours of in-person observations). Families recruited from the case-study services had histories of significant injury dating from 2018 to 2020. We also collected and analysed locally available documentation relating to candour and being open. Study phase 3: interpretation We conducted five interpretive forums to inform the interpretation of findings. These were a forum with project advisors (n = 14), including families (n = 6), a family forum with several SP1b study participants (n = 5) and three service case-study forums, comprised of clinical and service managers and clinicians. Total forum participation was approximately n = 65. All data were managed using NVivo 20 (QSR International, Warrington, UK) and analysed concurrently by two researchers using a retroductive approach. This technique involved the ongoing examination and theorisation of findings to identify causal explanations for how, for whom, and in what ways OD might be improved. We used the five programme theories identified from the realist review to organise the analysis and reporting of our stakeholder interview and ethnographic case-study findings. Findings from our forums are included in the synthesis and discussion of findings. Results Literature reviews Our scoping review of policy documents (n = 39) identified a shift from a paternalistic view of injured families as passive recipients of care to active contributors in reviews, investigations, learning and quality improvement. Two overlapping policy trajectories were identified: one related to the Duty of Candour (DoC) and one related to maternity safety more widely. Seven themes were identified: building trust in organisations; improving systems of care and ensuring accountability; improving the safety of maternity care and saying sorry; shifting to individualised, relational care; enhancing communication; conceptualising families as active partners rather than passive recipients; and enabling families to guide the process. Although the progression of how family involvement is discussed and considered in policy is moving in a positive direction, we note the opportunity for future, specific, actionable recommendations to ensure these ideals translate into practice. In the realist synthesis, documents (n = 39) were appraised for ‘fitness-for-purpose’, that together documented primary evidence of 21 OD improvement interventions from which we identified 5 initial programme theories. Interventions documented were predominantly from USA, Australasia, and, more recently, UK sources. We identified limited evidence of the effectiveness of interventions documented. We found a difference between interventions that were adjuncts to more general safety improvement projects, and organisation-wide interventions focused on post-incident communication and care of injured families. Identified programme theories were: receiving a meaningful acknowledgement of the harm that has happened, being involved during the review/investigation process, making sense of what happened, receiving care from clinicians who are skilled and feel psychologically safe during post-incident communication and knowing that things have changed because of what has happened. Findings by programme theory Receiving a meaningful acknowledgement of the harm that has happened National stakeholders described factors that prevented or slowed improvements in initial post-incident communication and ongoing care of injured families. These were: the risks of litigation and reputational damage which may be associated with an apology and the obligation to be candid. This was particularly challenging when the extent or circumstances of injury were uncertain. Variation in the confidence and willingness of clinicians to undertake initial and ongoing disclosure with families was noted across the case studies. Alongside general medicolegal and ethical challenges to disclosure improvements, wider erosion of compassionate disclosure with families in relation to the escalation of organisational compliance in maternity safety initiatives was noted by stakeholders. Interviews with families on their post-incident experiences (2007–11) highlighted an ongoing lack of compassionate care and of prompt disclosure in many services. Many families distrusted post-incident communication, suspecting that information was being withheld. In the case-study services, the main concern for OD leads was the recovery of family trust in the service. Here, the tension between disclosure as a mandated directive and as ongoing communication was notable, with lack of investment and organisational support for the latter. A significant context of OD work was the churn of work schedules and the speed of family transfers. This complicated efforts to develop consistency of communication and care across initial, mandated and ongoing post-incident meetings, particularly where the uniqueness and flux in the needs of harmed families were paramount and families were already distrustful. These conditions led to a situation where OD was sustained as an individual and selective initiative conducted by some clinicians with some families. Being involved during the review/investigation process We examined experiences of the implementation of family engagement through the Perinatal Mortality Review Tool (PMRT) and independent Health Safety Investigation Branch (HSIB) reviews/investigations from national, in-depth, case-study perspectives. We found PMRT implementation sometimes lacked relational care for families. Additionally, families were sometimes suspicious of the independence of external incident reviews. The case-study services reported inadequacies in family inclusion, with limited proactive approaches to family involvement. A range of family involvement approaches and rationales for involvement were found across and within the case-study services, with an emphasis on families as contributing value to organisational learning for safety improvement. The tension felt by clinicians between sharing uncertain knowledge of an incident with a family and sustaining OD is identified, as is the tension between the different goals of families and services, with the former desiring answers about their case and the latter seeking system-based learning for ongoing safety improvement. Making sense of what happened We explore the practices of knowledge construction in incidents and the management of this knowledge from the perspectives of national stakeholders, staff and families. The impact of widespread organisational defensiveness over documentation sent to families, along with confusion over the purpose of reports, generated distrust. Nationally, the poor quality or inaccuracies in clinical records exacerbated differences between service and family perspectives. In the crafting of reports, during ongoing family debriefings on report findings and through informal avenues and networks, the support for families to make sense of what happened could sometimes be recovered. However, we identify the privilege and capacity required for families to gather information and garner personal networks and expertise independently of services for this to take place. Receiving care from clinicians who are skilled and feel psychologically safe during post-incident communication We identified a national underinvestment in the training of clinicians in the care of injured families and in specialist OD skills. Interviews with junior clinicians, including Band 5/6 midwives; obstetric trainees and clinical fellows, highlighted the importance of early, non-judgemental, post-incident support for junior staff. The ongoing impact of avoidable harm on clinicians is examined, along with the impact of the limited involvement of staff in Trust-level investigation and review processes. We mapped the organisation and reported use of post-incident staff support for the three case-study services and found that debriefs, organised within a few weeks of the incident, and opportunities for meeting with families were most valued by staff. Services designed or commissioned by organisations without consultation with front-line staff themselves were underused and there was also a tendency for expert clinicians to see OD work as a personal rather than a professional or service imperative. Knowing that things have changed because of what has happened The importance for injured families and staff involved in an incident to see learning and service change following an incident was clear in national and case-study findings. Demonstrating that changes were in progress was key to a service demonstrating trustworthiness to the injured family. Some injured families felt a personal responsibility to ensure that change was secured. However, in most cases, services did not maintain contact with families after their review or investigation debriefs. For some clinical leads, there was a tension between ‘quick wins’ and protracted, significant, service investment. For wider staff groups, there was a lack of effective service-level communication strategies for updating on learning and change from incidents. Embedded, ongoing multidisciplinary team meetings, where non-judgemental discussion of incidents and their effects could take place, were identified as important for establishing a wider culture of openness. The extent and tone of clinical governance (CG) outreach to front-line staff were also significant in shaping staff attitudes and behaviours towards incidents and harmed families. Discussion Realist analysis identified the significant factors and contexts that impacted efforts to strengthen OD in maternity care. We explored several layers of context influencing the progress of this work. Nationally, we identified an ongoing tension between policy prompting OD and a medicolegal context where this openness continued to place clinicians and services at reputational or legal risk. Trust-level clinical leadership and the maturation of related service approaches (notably, family and patient involvement expertise and access to post-pregnancy support pathways) played a significant role in supporting OD. For families, variations in post-incident communication and care depended on two main factors: first, the assignment of an incident to one or more national maternity safety improvement programmes that entailed particular expectations of, and processes for, family involvement, and second, the capacity of a family to proactively seek out explanations and to foster relationships for personalised support from some clinicians. In the case-study services, where some harmed families were proactive in demanding a hearing and ongoing care, and where individual clinicians reached personal judgements on a family’s entitlement to this, examples of improved OD were observed. Overall, variations in post-incident communication and support for families were explained by a lack of service investment and by individual differences in attitudes to risk and family entitlement from clinicians. Conclusions This study is the first to establish a national overview and in-depth analysis of the progress of interventions intended to support OD with families. It provides an evidence base of experiences of harmed families (incidents ranging from 2007 to 2021) and of clinicians and managers working in this field (2020–1). There are growing calls for service-level improvements in responsiveness to the experiences and needs of families post incident as well as to their calls for greater openness. However, we find that without dedicated investment in and focus on the post-incident care of families and the emotional and organisational demands of this work on clinicians; without an understanding of these needs by external agencies incentivising improvement; and without national revision in the medicolegal landscape where this work happens, candour about harm in health care will continue to divide the interests of families, staff and services. Research gaps and recommendations Research was conducted immediately after the COVID-19 pandemic, with services under considerable strain. Three high-performing services were recruited for the observational research; therefore, generalisation from findings is limited. Access to observe external (HSIB) investigations was not possible. Despite ongoing revisions to the patient and public involvement (PPI) strategy, families often marginalised by maternity services remain under-represented in this study. A multi-methods study across English maternity services to establish the validity of findings and family recruitment strategies ensuring diversity are recommended for the future. Study registration This study is registered as PROSPERO CRD42020164061. The study has been assessed following RAMESES realist guidelines. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research Programme (NIHR award ref: 17/99/85) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 22. See the NIHR Funding and Awards website for further award information.

Abstract Background Despite Africa’s significant infectious disease burden, it is underrepresented in global vaccine clinical trials. While this trend is slowly reversing, it is important to recognize and mitigate the challenges that arise when conducting vaccine clinical trials in this environment. These challenges stem from a variety of factors peculiar to the population and may negatively impact adverse event collection and reporting if not properly addressed. Methods As a team of clinical researchers working within the MRCG (Medical Research Council Unit The Gambia), we have conducted 12 phase 1 to 3 vaccine trials over the past 10 years. In this article, we discuss the challenges we face and the strategies we have developed to improve the collection and reporting of adverse events in low-income settings. Outcome. Healthcare-seeking behaviors in the Gambia are influenced by spiritual and cultural beliefs as well as barriers to accessing orthodox healthcare; participants in trials may resort to non-orthodox care, reducing the accuracy of reported adverse events. To address this, trial eligibility criteria prohibit self-treatment and herbal product use during trials. Instead, round-the-clock care is provided to trial participants, facilitating safety follow-up. Constraints in the healthcare system in the Gambia such as limitations in diagnostic tools limit the specificity of diagnosis when reporting adverse events. To overcome these challenges, the Medical Research Council Unit maintains a Clinical Services Department, offering medical care and diagnostic services to study participants. Sociocultural factors, including low literacy rates and social influences, impact adverse event collection. Solicited adverse events are collected during home visits on paper-based or electronic report forms. Community engagement meetings are held before each study starts to inform community stakeholders about the study and answer any questions they may have. These meetings ensure that influential members of the community understand the purpose of the study and the risks and benefits of participating in the trial. This understanding makes them more likely to support participation within their communities. Conclusion Conducting ethical vaccine clinical trials in resource-limited settings requires strategies to accurately collect and report adverse events. Our experiences from the Gambia offer insights into adverse event collection in these settings.

Abstract Adverse events suffer from poor reporting within randomised controlled trials, despite them being crucial to the evaluation of a treatment. A recent update to the CONSORT harms checklist aims to improve reporting by providing structure and consistency to the information presented. We propose an extension wherein harms would be reported in conjunction with effectiveness outcome(s) rather than in silo to provide a more complete picture of the evidence acquired within a trial. Benefit-risk methods are designed to simultaneously consider both benefits and risks, and therefore, we believe these methods could be implemented to improve the prominence of adverse events when reporting trials. The aim of this article is to use case studies to demonstrate the practical utility of benefit-risk methods to present adverse events results alongside effectiveness results. Two randomised controlled trials have been selected as case studies, the Option-DM trial and the SANAD II trial. Using a previous review, a shortlist of 17 benefit-risk methods which could potentially be used for reporting RCTs was created. From this shortlist, three benefit-risk methods are applied across the two case studies. We selected these methods for their usefulness to achieve the aim of this paper and which are commonly used in the literature. The methods selected were the Benefit-Risk Action Team (BRAT) Framework, net clinical benefit (NCB), and the Outcome Measures in Rheumatology (OMERACT) 3 × 3 table. Results using the benefit-risk method added further context and detail to the clinical summaries made from the trials. In the case of the SANAD II trial, the clinicians concluded that despite the primary outcome being improved by the treatment, the increase in adverse events negated the improvement and the treatment was therefore not recommended. The benefit-risk methods applied to this case study outlined the data that this decision was based on in a clear and transparent way. Using benefit-risk methods to report the results of trials can increase the prominence of adverse event results by presenting them alongside the primary efficacy/effectiveness outcomes. This ensures that all the factors which would be used to determine whether a treatment would be recommended are transparent to the reader.

Since 2019, severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has been widespread in the world, causing about 770 million infecting and 6.9 million deaths. Vaccines against SARS-CoV-2 infection have become the main way to prevent the severe SARS-CoV-2. The use of SARS-CoV-2 vaccine has substantial protection against the serious consequences of SARS-CoV-2 infection, but multiple systemic adverse reactions can occur after the use of SARS-CoV-2 vaccine. More and more studies have shown that SARS-CoV-2 vaccine caused lesions of ocular conjunctiva, cornea, sclera, uvea, retina and optic nerve tissue and resulted in damage to visual function. In this paper, the classification and characteristics of SARS-CoV-2 vaccines and related studies on ocular tissue lesions were reviewed, hoping to better understand the ocular adverse reactions of SARS-CoV-2 vaccine and provide some theoretical guidance for the prevention and treatment of ocular tissue damage caused by SARS-COV-2 vaccine.

Introduction and purpose: Over the past two decades, the management of severe asthma shifted from high doses of inhaled and oral corticosteroids to targeted biologic agents. Adverse effects of treatment with monoclonal antibodies are not yet fully characterised. The aim of this paper is to provide a comprehensive review of the adverse effects of the FDA-approved monoclonal antibodies in the treatment of moderate-to-severe asthma, including omalizumab, benralizumab, dupilumab, mepolizumab, reslizumab, tezepelumab. Material and methods of research: A thorough literature review was performed using PubMed Web of Science and Embase, employing key words related to monoclonal antibodies, asthma and adverse effects. Description of the state of knowledge: Omalizumab and mepolizumab have black box warning on the risk of anaphylaxis. Due to scarcity of data, no causal association between the use of monoclonal antibodies and risk of malignancy can be established. The most common adverse effects of biologic agents in severe asthma include upper respiratory tract infections, nasopharyngitis and asthma worsening. Conclusions: Overall, monoclonal antibodies have a favourable safety profile, with certain risk of side effects remains present, and is variable for the different molecules. More studies of asthmatic patients treated with monoclonal antibodies are needed to spot rare adverse events and those developing over longer time.

Introduction: The World Health Organization (WHO) recommends vaccination against hepatitis B as soon as possible following birth for all infants, regardless of prematurity. Hepatitis B vaccination at birth is clearly justified, represents a crucial step in the global control of perinatally acquired hepatitis B and there are no safety concerns in infants born at term. However, there is limited information on the safety of the hepatitis B vaccine in preterm infants, whose immune responses and morbidity risk differ from those in infants born at term. Objectives: The objectives of this paper are to systematically review the literature regarding the safety and risk of adverse events following immunisation (AEFIs) associated with the administration of the hepatitis B vaccine (monovalent or as part of a combination vaccine) to preterm infants. Methods: We performed a search for relevant papers published between 1 January 2002 and 30 March 2023 in the Ovid MEDLINE, Ovid Embase, Cochrane Central Register of Controlled Trials and CINAHL Plus databases. Two authors independently reviewed and analysed each article to include in the systematic review. Narrative synthesis is presented. Results: Twenty-one relevant papers were identified and included in this systematic review. The vast majority of data pertained to multi-antigen (combination) vaccine preparations and vaccination episodes from 6 weeks of age onwards. We found no publications investigating the timing of the birth dose of the hepatitis B vaccine, and AEFI reporting was exclusively short-term (hours to days following administration). There was substantial variability in the reported rate of AEFIs between studies, ranging from 0% to 96%. Regardless of frequency, AEFIs were mostly minor and included injection site reactions, temperature instability and self-limiting cardiorespiratory events. Six studies reported serious adverse events (SAEs) such as the requirement for escalation of respiratory support. However, these occurred predominantly in high-risk infant populations and were rare (~1%). Using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach, the certainty of evidence was assessed as very low. Conclusions: Despite substantial variability between the relatively small number of published studies in terms of cohort selection, definitions, vaccine preparations and reporting, hepatitis B-containing vaccines (mostly as combination vaccines) appear to be relatively well tolerated in preterm infants from 6 weeks of age. Research focusing on the safety of hepatitis B vaccine in preterm infants specifically within 7 days of birth is lacking, particularly regarding long-term morbidity risk. Further research in this area is required.

Adverse events after surgery not only affect the patient’s recovery but also increase the burden on doctors and patients due to prolonged hospitalization. Predicting adverse events from patient data before surgery with a machine learning method is highly expected. It is difficult to collect a large amount of patient data since the number of surgeries in a year is limited and predict the occurrence of adverse events accurately since patient data are imbalanced data. To improve the accuracy of adverse event prediction, this paper proposes data generation with Filtered $\beta $ -VAE for the preoperative prediction of adverse events. Filtered $\beta $ -VAE has filters by the reconstruction error and by a machine learning method. After $\beta $ -VAE generates minority class data, the two layers of filtering are used to remove low-quality minority class data that have little contribution to the adverse event prediction. In the evaluations, patient data obtained from Tokyo Dental University Ichikawa General Hospital were used. The proposed method can predict adverse events with a recall of 0.848, which is 5.6% more accurate than existing methods. The effects of filtering in Filtered $\beta $ -VAE are visualized, and the reasons for the improvement in prediction accuracy are clarified. Furthermore, this paper shows that $\beta $ -VAE can generate arbitrary patient data even in table data, corresponding to the distribution of the original patient data.

Abstract Understanding the factors that influence people’s decisions regarding vaccination is essential to promote vaccination. We aimed to clarify the motivations for receiving booster vaccines. We conducted a paper-based questionnaire distributed during January–February 2022 involving students and faculty staff who received the first COVID-19 vaccination at the mass vaccination program during June–September 2021 at Keio University. A total of 1725 participants were enrolled, and all completed the survey. Among these, 64.9% reported a significant adverse event (AEs) affecting daily life after the second vaccine. “Fear of severe COVID-19 illness” (72.6%) was the most common reason for getting vaccinated, followed by “concern of infecting others” (68.4%) and “fear of COVID-19 infection itself” (68.3%). Television emerged as the most influential source of information (80%), followed by university information (50.2%) and social networking sites (42.8%). Multivariate analysis revealed “fear of severe COVID-19 illness”, “fear of COVID-19 infection itself”, and “trust in the efficacy and safety of the vaccines in general” were significantly correlated with willingness to receive paid vaccinations. The severity of AEs and source of information were not related to participants’ willingness to receive booster vaccinations. Participants with positive reasons for vaccination were more likely to accept a third dose.

Objective: Phenylketonuria (PKU) is a metabolic disorder necessitating lifelong management to prevent severe neurological impairments. This paper synthesises clinical practices from Italian specialist centres to delineate a unified approach for administering pegvaliase, a novel enzyme replacement therapy for PKU. Methods: Virtual meetings convened in September 2022, gathering a steering committee (SC) of experts from five Italian centres specialising in PKU. The SC reviewed, and discussed clinical practices, and formulated recommendations for pegvaliase treatment. Results: The SC outlined a comprehensive treatment roadmap for PKU management with pegvaliase, emphasising the importance of multidisciplinary care teams, patient selection, pre-treatment evaluation, and education. Recommendations include initial hospital-based pegvaliase administration, regular monitoring of phenylalanine and tyrosine levels, dietary adjustments, and management of adverse events. A consensus was reached on the need for a digital database to manage treatment plans and enhance communication between healthcare professionals and patients. Conclusion: The expert panel's consensus highlights the complexity of PKU management and the necessity for a coordinated, patient-centred approach. The recommendations aim to standardise care across Italian centres and provide a framework for integrating pegvaliase therapy into clinical practice, potentially informing international guidelines. Further research is warranted to evaluate the long-term impact of these practices on patient outcomes and quality of life.

Abstract Pancreatic stones are the result of pathophysiologic changes in chronic pancreatitis with an incidence of more than 90%. At present, pancreatic extracorporeal shock wave lithotripsy (P-ESWL) can be used as the first-line treatment for large or complex stones. Although a large number of studies have proven the safety and effectiveness of P-ESWL, we should also pay attention to postoperative adverse events, mainly due to the scattering of shock waves in the conduction pathway. Adverse events can be classified as either complications or transient adverse events according to the severity. Because the anatomic location of organs along the shock wave conducting pathway differs greatly, adverse events after P-ESWL are varied and difficult to predict. This paper outlines the mechanism, definition, classification, management and risk factors for adverse events related to P-ESWL. It also discusses the technique of P-ESWL, indications and contraindications of P-ESWL, and adverse events in special populations.

Sedation is common during digestive endoscopy to provide comfort and pain relief for patients. However, the use of sedation in endoscopy also poses potential risks, and recent issues have been raised regarding its safety and administration. This literature review paper will discuss the most recent developments in the field of sedation in digestive endoscopy, including the adverse events that might be associated with sedation and how to manage it, the legal issues associated with administration, the impact of COVID-19 on sedation practices, and sedation in special situations. It will also touch upon the current guidelines and recommendations for sedation, including the importance of patient selection and monitoring and the need for training and certification for endoscopists administering sedation. The review will also analyse studies evaluating the safety and efficacy of various sedation techniques, including propofol, midazolam, and others. It will examine the benefits and drawbacks of these agents.

Endoscopic esophageal stent placement is an effective palliative treatment for malignant strictures and has also been successfully used for benign indications, including esophageal refractory strictures and iatrogenic leaks and perforations. Despite several decades of evolution and the wide variety of esophageal stents available to choose from, an ideal stent that is both effective and without adverse events such as stent migration, tissue ingrowth, or pressure necrosis has yet to be developed. This paper is an overview of how this evolution happened, and it also addresses the characteristics of some of the currently available stents, like their material and construction, delivery device, radial and axial force pattern, covering and size which may help to understand and avoid the occurrence of adverse events. The insertion delivery systems and techniques of placement of an esophageal self-expandable metal stent are reviewed, as well as some tips and tricks regarding placement and management of adverse events.

In the past, the doctor’s knowledge, clinical skills and judgement were the ‘main impetus for treatment decisions, therapy assessment and medical progress’, with the ‘emphasis being on protecting and restoring human well-being’. While the advent of evidence-based medicine (EBM) and the increased use of innovative technology have undoubtedly enhanced the practice of medicine and dentistry, overzealous reliance and application of these carries a risk of overshadowing the human aspects of clinical judgement and decision making. This paper uses a dental example to illustrate and caution practitioners against losing site of the patient in their quest to treat the condition. It is important for any practitioner who engages in radiology beyond conventional 2D imaging being liable to examine it in its entirety and to report on findings from the entire field of view. They may need theoretical and practical training to do this, as failure to detect and manage any pathology is considered negligence and is grounds for litigation. Alternatively, they can refer the patient to a trained radiologist if they would prefer an expert opinion. The area of dental radiography will be used for the following ethical and legal debate; however, the principles questioned could be applied to all specialist referrals. The ethical question relates to the issue of how to manage a patient where the clinicians based their treatment on the diagnosis and report given to them by an expert in some other related specialist medical field, but where the report was erroneous, resulting in an unforeseen adverse outcome. What makes the case more complex was the contradiction between the clinical judgement and the radiological findings, which only became evident at the time of surgery.

Abstract Background Healthcare is not without risk. Despite two decades of policy focus and improvement efforts, the global incidence of harm remains stubbornly persistent, with estimates suggesting that 10% of hospital patients are affected by adverse events. Methods We explore how current investigative responses can compound the harm for all those affected—patients, families, health professionals and organizations—by neglecting to appreciate and respond to the human impacts. We suggest that the risk of compounded harm may be reduced when investigations respond to the need for healing alongside system learning, with the former having been consistently neglected. Discussion We argue that incident responses must be conceived within a relational as well as a regulatory framework, and that this—a restorative approach—has the potential to radically shift the focus, conduct and outcomes of investigative processes. Conclusion The identification of the preconditions and mechanisms that enable the success of restorative approaches in global health systems and legal contexts is required if their demonstrated potential is to be realized on a larger scale. The policy must be co‐created by all those who will be affected by reforms and be guided by restorative principles. Patient or Public Contribution This viewpoint represents an international collaboration between a clinician academic, safety scientist and harmed patient and family members. The paper incorporates key findings and definitions from New Zealand's restorative response to surgical mesh harm, which was co‐designed with patient advocates, academics and clinicians.

Epidermal growth factor receptor (EGFR) mutations are the most common oncogenic driver in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are widely used in the treatment of lung cancer, especially in the first-line treatment of advanced NSCLC, and EGFR-TKIs monotherapy has achieved better efficacy and tolerability compared with standard chemotherapy. However, acquired resistance to EGFR-TKIs and associated adverse events pose a significant obstacle to targeted lung cancer therapy. Therefore, there is an urgent need to seek effective interventions to overcome these limitations. Natural medicines have shown potential therapeutic advantages in reversing acquired resistance to EGFR-TKIs and reducing adverse events, bringing new options and directions for EGFR-TKIs combination therapy. In this paper, we systematically demonstrated the resistance mechanism of EGFR-TKIs, the clinical strategy of each generation of EGFR-TKIs in the synergistic treatment of NSCLC, the treatment-related adverse events of EGFR-TKIs, and the potential role of traditional Chinese medicine in overcoming the resistance and adverse reactions of EGFR-TKIs. Herbs and active compounds have the potential to act synergistically through multiple pathways and multiple mechanisms of overall regulation, combined with targeted therapy, and are expected to be an innovative model for NSCLC treatment.

Background: The effect of mild changes in CO2 levels to organ perfusion and tissue inflammation are well known, whereas an influence of hypercapnia under general anesthesia on adverse events as nausea and vomiting, or length of hospital stay is barely examined. The goal of our meta-analysis was to identify possibly positive effects of hypercapnia versus normocapnia in general anesthesia in adult patients. Methods: We conducted a systematic review of parallel-arm randomised controlled trials comparing hypercapnia versus normocapnia in adult patients undergoing general anesthesia. In July 2018 and September 2019 we searched “CENTRAL‿, “MEDLINE‿, and “Embase‿, checked reference lists of all included studies and relevant systematic reviews for additional references to trials. Two review authors independently assessed trials for inclusion, extracted data, and completed a “Risk of bias‿ assessment for all included studies. Results: Our search identified 297 records after abstract screening 30 full-text papers remained for further examination. Ten publications met our inclusion criteria and were used for narrative description of this systematic review. Three studies were eligible for the meta-analysis normocapnia versus hypercapnia with the outcomes: time to extubation and adverse events. On average, time to extubation was significantly reduced in the hypercapnia group with a mean difference 3.78 (95% CI 0.85 to 6.71). No difference was found regarding adverse events. Conclusions: The findings of our study do not enable us to produce evidence of a positive influence of increased CO2 partial pressure levels during general anesthesia. A well-planned, adequately powered randomized controlled trial would be desirable in the future.

Abstract Aim To identify outcomes of missed nursing care for adult patients. Design A five‐stage rapid review process was conducted as follows: refining the question, retrieving relevant studies, determining the studies to be included, organizing the data and synthesizing the results. Methods Papers published between 2010–2020 that focused on the UK, Europe, the USA and Oceania were searched for keywords in the title and abstract in major databases. The articles that identified the impact of missed nursing care on adults in health care were selected. Results Seventeen articles met the criteria. Major impacts of missed care in adult settings were increases in mortality, adverse events and failure to maintain. These same studies also identified a range of causative factors linked to ward environment, inadequate staffing levels and skills mix although are inconclusive. Solutions include continuing education, ward and work re‐design, and appropriate skill level.

Abstract ICD-11 provides a promising new way to capture healthcare-related harm or injury. In this paper, we elaborate on the framework for describing healthcare-related events where there is a presumed causal link between an event and underlying healthcare-related factors. The three-part model for describing healthcare-related harm or injury in ICD-11 consists of (1) a healthcare-related activity that is the cause of injury or other harm (selected from Chapter 23 of ICD-11); (2) a mode or mechanism of injury or harm, related to the underlying cause (also from Chapter 23 of ICD-11); and (3) the harmful consequences of the event to the patient, selected from any of Chapters 1 through 22 of ICD-11 (most importantly, the injury or harm experienced by the patient). Concepts from these three elements are linked/clustered through postcoordination to reflect the three-part model in a single coded expression. ICD-11 contains many novel features, and the three-part model described here for healthcare-related adverse events is a notable example.

The long-term use of psychopharmacology medications in autism spectrum disorder (ASD) hitherto remains controversial due to a lack of evidence about safety and tolerability. In this regard, genotyping the metabolizing enzyme cytochrome P450 (CYP) 2D6, especially its extreme phenotypes, could help to prevent drug-related adverse reactions or adverse events (AEs). There are several medications warranting CYP2D6 screening that are consumed by people with ASD, such as risperidone and aripiprazole to name a few. A naturalistic observational study was carried out in participants with ASD to analyze the influence of the CYP2D6 phenotype in drug tolerability using a local pharmacovigilance system created for this study. In this case, AEs were identified from participants’ electronic health records (EHRs) and paper registries. Other variables were collected: socio-demographic information, comorbidities, and psychopharmacology prescriptions (polypharmacy defined as ≥4 simultaneous prescriptions) and doses. The genetic analysis included allelic discrimination (CYP2D6*1, *2, *3, *4, *5, *6, *10, *17, and *41) and copy number variations. All of these were used to determine theoretical phenotypes of the metabolic profiles: poor (PM); intermediate (IM); normal (NM); and ultra-rapid (UM). Sex differences were analyzed. A total of 71 participants (30 ± 10 years old, 82% male, 45% CYP2D6 NM phenotype (32 participants)) with a median of 3 (IQR 2–4) comorbidities per person, mainly urinary incontinence (32%) and constipation (22%), were included. CYP2D6 UM showed the highest rate of polypharmacy, whilst, IM participants had the highest rates of neurological and psychiatric AEs, even worse if a CYP2D6 inhibitor drug was prescribed simultaneously. CYP2D6 pharmacogenomics and the monitoring of new antipsychotic prescriptions may make a difference in medication safety in adults with ASD. Particularly in those with psychopharmacology polymedication, it can help with AE avoidance and understanding.

In recent years, the U.S. Food and Drug Administration (FDA) has seen an increase in microfluidic medical device submissions, likely stemming from recent advancements in microfluidic technologies. This recent trend has only been enhanced during the COVID-19 pandemic, as microfluidic-based test kits have been used for diagnosis. To better understand the implications of this emerging technology, device submissions to the FDA from 2015 to 2021 containing microfluidic technologies have been systematically reviewed to identify trends in microfluidic medical applications, performance tests, standards used, fabrication techniques, materials, and flow systems. More than 80% of devices with microfluidic platforms were found to be diagnostic in nature, with lateral flow systems accounting for about 35% of all identified microfluidic devices. A targeted analysis of over 40,000 adverse event reports linked to microfluidic technologies revealed that flow, operation, and data output related failures are the most common failure modes for these device types. Lastly, this paper highlights key considerations for developing new protocols for various microfluidic applications that use certain analytes (e.g., blood, urine, nasal-pharyngeal swab), materials, flow, and detection mechanisms. We anticipate that these considerations would help facilitate innovation in microfluidic-based medical devices.

There is an erratum to this paper published in Veterinary Evidence Vol 7, Issue 2 (2022): 10.18849/VE.V7I2.627 Objective: To assess outcomes of a limited period (7 months) of remote video consultation with prescribing of prescription-only (POM) or prescription-only-veterinary (POM-V) medications by Royal College of Veterinary Surgeons (RCVS) registered veterinary surgeons to UK clients via a veterinary telemedicine smartphone application. Background: Objective evidence is needed to inform the veterinary profession on the impact that remote prescribing, without physical examination in person, has on animal health and welfare. During the COVID-19 pandemic, the RCVS allowed remote prescribing temporarily. Methods: Clinical records from all veterinary video consultations from 1 April–31 October 2020 were reviewed. Details were assessed pertaining to: signalment, body system / disease categories managed, referrals into practice, medication classes prescribed and outcomes following POM-V / POM medications. Records of adverse events and antimicrobial prescribing were reviewed. Results: 16.6% (3,541/21,383) of video consults had a POM-V / POM prescribed; with a (mild) adverse event rate of 0.8% (30/3541). Antibacterials were prescribed in 5.88% of all consultations (1,258/21,383), 99.3% (1249/1258) being first line. Follow-up on prescribing was available in 67.7% (2,399/3541) of cases. 89% (2135/2399) of all known treatment outcomes were complete or had an expected response to treatment. Dermatological disease was the most common body system / disease category seen and prescribed for. Conclusion: Low prescribing rates (including antibacterials) were recorded, treatments were efficacious and no harm was done by prescribing remotely via a veterinary video consult app. Application: Veterinary surgeons and governing bodies are invited to use the information provided in this clinical audit to inform decisions on the suitability of remote consultations and prescribing in veterinary medicine.

Antipsychotic polypharmacy/drug combination treatment (APP) is a remarkably common practice in the schizophrenia context, given the lack of general support in treatment Guidelines. There is also a vast literature on APP outcomes, but a paucity of high-quality evidence-based data to guide and optimize adequate use of APP. This seems particularly true regarding many pharmacology-based considerations involved in APP treatment strategies. This paper first briefly summarizes clinical literature related to the use of APP. Against this backdrop, the pharmacological target profile features are then described of frequently used antipsychotic agents, in relation to estimated free plasma exposure levels at clinically efficacious dosing. APP strategies based on the properties of these drugs are then scrutinized and gauged within the background literature framework. The anticipated usefulness of APP from the pharmacological standpoint is detailed regarding efficacy, adverse effect (AE)/tolerability, and safety perspective, including why, when, and how it may be used to its advantage. For the purpose, a number of theoretically beneficial combinations as well as instances with suboptimal—and even futile—APP approaches are exemplified and discussed from the rational pharmacodynamic and pharmacokinetic pros and cons point-of-view. In this exposé, particular attention is paid to the utility and features of 3rd Generation Antipsychotic dopamine (DA) D2-D3 agonists within an APP setting.

The purpose of this paper is to renew interest and attention to the medical history, prescription, and/or use of drugs during dental practice. The work analyzes the issue of the use of drugs in dentistry from both a clinical and a medical–legal point of view. The laws governing the matter were also taken into consideration, relating them to the roles of prescriber and user that the dentist can acquire. Analysis of various aspects of this matter demonstrates that it is necessary for dentists to know the drugs and medical substances, their characteristics and properties, related effects, and interactions in order to use them appropriately and adequately. Knowledge of interferences, reactions, and adverse events or complications helps to reduce errors and protect patients’ health. Furthermore, knowledge of the national and international reference standards relating to the use of drugs leads to a reduction in medico–legal questions. In conclusion, knowledge and adequate and appropriate use of drugs reduces the possibility of accidents, adverse events, medico–legal consequences, and disputes with patients. Documented and traceable choices allow the analysis and valuation of professional conduct. Authors perceived the topic of informed consent of patients as relevant to the adequate procedure of prescribing drugs related to dentistry practice; therefore, representative conditions of patients at risk should be illustrated in practice. Legal duties related to physician drug prescription and use must be considered and carefully checked.