Mutational landscape, inhibitor development, and health-care burden in non-severe haemophilia A: A single-centre Australian experience.

AIM: To characterise non-severe haemophilia A (HA) patients enrolled on the Australian Bleeding Disorders Registry (ABDR) treated through a state-wide Haemophilia Treatment Centre (HTC) with respect to their mutational profile, inhibitor risk and health-care burden. METHOD: We conducted a single-centre observational study of all non-severe HA patients treated at the Alfred Health HTC registered on the ABDR as of the 26th July 2023. Data were extracted from the ABDR and electronic medical record (EMR) regarding demographics, severity, genetic testing, treatment, inhibitors, bleeding events and procedures. Inhibitor risk was calculated as a function of exposure days (EDs) of FVIII replacement. RESULTS: There were 289 non-severe HA patients treated at the Alfred HTC registered on the ABDR as of July 2023, all of whom were adult patients aged > 18 years old. Genotyping had been performed in 228/289 (78.9%). Of the inhibitor analysis population, 14/193 (7.3%) had an inhibitor. The cumulative incidence of inhibitor development at 75 EDs was 31% (95% CI 13%-46%). The median cost of bypassing agents per inhibitor patient was $57,087.50/year. CONCLUSION: These results demonstrate a relatively high inhibitor prevalence and incidence risk in non-severe HA compared to previously published work, although this may partly reflect a smaller population size. High rates of genotyping have allowed representative mutational characterisation. The burden of care imposed by non-severe HA in terms of bleeding events, procedures and bypassing agent cost is larger than expected, particularly within the inhibitor population.

PET-CT-guided versus CT-guided biopsy in suspected malignant pleural thickening: a randomised trial.

BACKGROUND: Pleural biopsy is the gold standard for diagnosis of pleural malignancy but a significant proportion will have an inconclusive biopsy despite ongoing clinical suspicion of malignancy. We investigated whether positron emission tomography-computed tomography (PET-CT) targeted pleural biopsy is superior to standard CT-guided pleural biopsy following an initial non-diagnostic biopsy. METHODS: The TARGET trial was a multicentre, parallel group randomised trial. Patients with a previous inconclusive pleural biopsy but an ongoing suspicion of pleural malignancy were randomised (1:1) to receive either CT-guided biopsy (standard care) or PET-CT followed by a targeted CT biopsy (intervention). The primary outcome was pleural malignancy correctly identified from the trial biopsy. RESULTS: Between September 2015 and September 2018, 59 participants were randomised from eight UK hospital sites: 29 to CT-only followed by targeted biopsy and 30 to PET-CT followed by targeted biopsy. The proportion of pleural malignancy correctly identified was similar between the groups (risk ratio 1.03 (95% CI 0.83-1.29); p=0.77). The sensitivity of the trial biopsy to identify pleural malignancy was 79% (95% CI 54-94%) in the CT-only group versus 81% (95% CI 54-96%) in the PET-CT group. CONCLUSIONS: The results do not support the practice of PET-CT to guide pleural biopsies in patients with a previous non-diagnostic biopsy. The diagnostic sensitivity in the CT-only group was higher than anticipated and supports the practice of repeating a CT-guided biopsy following an inconclusive result if clinical suspicion of malignancy persists.

What do Retraction Notices Reveal About Institutional Investigations into Allegations Underlying Retractions?

Academic journal publications may be retracted following institutional investigations that confirm allegations of research misconduct. Retraction notices can provide insight into the role institutional investigations play in the decision to retract a publication. Through a content analysis of 7,318 retraction notices published between 1927 and 2019 and indexed by the Web of Science, we found that most retraction notices (73.7%) provided no information about institutional investigations that may have led to retractions. A minority of the retraction notices (26.3%) mentioned an institutional investigation either by journal authorities (12.1%), research performing organizations (10.3%), joint institutions (1.9%), research integrity and ethics governing bodies (1.0%), third-party institutions (0.5%), unspecified institutions (0.4%), or research funding organizations (0.1%). Comparing retraction notices issued before and after the introduction of retraction guidelines by the Committee on Publication Ethics (COPE) in 2009 revealed that those published after the guidelines' publication were more likely to report investigations by journal authorities. Comparing retraction notices from different disciplines revealed that those from social sciences and the humanities were more likely to disclose investigations by research performing organizations than those from biomedical and natural sciences. Based on these findings, we suggest that the COPE retraction guidelines in the future make it mandatory to disclose in retraction notices institutional investigations leading to retractions.

Co-creating Research Integrity Education Guidelines for Research Institutions.

To foster research integrity (RI), research institutions should develop a continuous RI education approach, addressing various target groups. To support institutions to achieve this, we developed RI education guidelines together with RI experts and research administrators, exploring similarities and differences in recommendations across target groups, as well as recommendations about RI education using approaches other than formal RI training. We used an iterative co-creative process. We conducted four half-day online co-creation workshops with 16 participants in total, which were informed by the RI education evidence-base. In the first two workshops, participants generated ideas for guidelines' content, focusing on different target groups and various approaches to RI education. Based on this content we developed first drafts of the guidelines. Participants in the third and fourth workshop refined those drafts. We next organized a working group which further prioritized, reorganized, and optimized the content of the guidelines. We developed four guidelines on RI education focusing on (a) bachelor, master and PhD students; (b) post-doctorate and senior researchers; (c) other RI stakeholders; as well as (d) continuous RI education. Across guidelines, we recommend mandatory RI training; follow-up refresher training; informal discussions about RI; appropriate rewards and incentives for active participation in RI education; and evaluation of RI educational events. Our work provides experience-based co-created guidance to research institutions on what to consider when developing a successful RI education strategy. Each guideline is offered as a distinct, publicly available tool in our toolbox ( www.sops4ri.eu/toolbox ) which institutions can access, adapt and implement to meet their institution-specific RI education needs.Trial registration https://osf.io/zej5b .

Optimal Dose of Intranasal Dexmedetomidine for Laceration Repair in Children: A Phase II Dose-Ranging Study.

STUDY OBJECTIVE: To determine the optimal sedative dose of intranasal dexmedetomidine for children undergoing laceration repair. METHODS: This dose-ranging study employing the Bayesian Continual Reassessment Method enrolled children aged 0 to 10 years with a single laceration (<5 cm), requiring single-layer closure, who received topical anesthetic. Children were administered 1, 2, 3, or 4 mcg/kg intranasal dexmedetomidine. The primary outcome was the proportion with adequate sedation (Pediatric Sedation State Scale score of 2 or 3 for ≥90% of the time from sterile preparation to tying of the last suture). Secondary outcomes included the Observational Scale of Behavior Distress-Revised (range: 0 [no distress] to 23.5 [maximal distress]), postprocedure length of stay, and adverse events. RESULTS: We enrolled 55 children (35/55 [64%] males; median [interquartile range {IQR}] age 4 [2, 6] years). At 1, 2, 3, and 4 mcg/kg intranasal dexmedetomidine, respectively, the proportion of participants "adequately" sedated was 1/3 (33%), 2/9 (22%), 13/21 (62%), and 12/21 (57%); the posterior mean (95% equitailed credible intervals) for the probability of adequate sedation was 0.38 (0.04, 0.82), 0.25 (0.05, 0.54), 0.61 (0.41, 0.80), and 0.57 (0.36, 0.76); the median (IQR) Observational Scale of Behavior Distress-Revised scores during suturing was 2.7 (0.3, 3), 0 (0, 3.8), 0.6 (0, 5), and 0 (0, 3.7); the median (IQR) postprocedure length of stay was 67 (60, 78), 76 (60, 100), 89 (76, 109), and 113 (76, 150) minutes. There was 1 adverse event, a decrease in oxygen saturation at 4 mcg/kg, which resolved with head repositioning. CONCLUSION: Despite limitations, such as our limited sample size and subjectivity in Pediatric Sedation State Scale scoring, sedation efficacy for 3 and 4 mcg/kg were similarly based on equitailed credible intervals suggesting either could be considered optimal.

The Contribution of Moral Case Deliberation to Teaching RCR to PhD Students.

Teaching responsible conduct of research (RCR) to PhD students is crucial for fostering responsible research practice. In this paper, we show how the use of Moral Case Deliberation-a case reflection method used in the Amsterdam UMC RCR PhD course-is particularity valuable to address three goals of RCR education: (1) making students aware of, and internalize, RCR principles and values, (2) supporting reflection on good conduct in personal daily practice, and (3) developing students' dialogical attitude and skills so that they can deliberate on RCR issues when they arise. What makes this method relevant for RCR education is the focus on values and personal motivations, the structured reflection on real experiences and dilemmas and the cultivation of participants' dialogical skills. During these structured conversations, students reflect on the personal motives that drive them to adhere to the principles of good science, thereby building connections between those principles and their personal values and motives. Moreover, by exploring personal questions and dilemmas related to RCR, they learn how to address these with colleagues and supervisors. The reflection on personal experiences with RCR issues and questions combined with the study of relevant normative frameworks, support students to act responsibly and to pursue RCR in their day-to-day research practice in spite of difficulties and external constraints.

A Shared Decision-Making Process Utilizing a Decision Coach in Pediatric Epilepsy Surgery.

BACKGROUND & RATIONALE: The process to evaluate candidacy for epilepsy surgery is lengthy and stressful for caregivers, therefore the decision can be challenging. There is not a lot of information in regard to how families of a child living with epilepsy navigate the stressful decision during surgical candidacy evaluation. With difficult decisions comes the possibility of increased decisional conflict in both the child and the family. METHODS: A project designed to provide greater knowledge to the family was conducted utilizing the shared decision-making (SDM) process to assist families in the decision-making during surgical candidacy evaluation; this was done using a decision coach, who is an unbiased health care professional, providing families with evidence-based information and support tools while supporting them in making decisions based on their values. RESULTS: Results reveal that 90% (45 of 50) of families offered a consult with the decision coach agreed to participate. For these families, 78% (35 of 45) felt they were ready to move forward with surgery after the consult and 22% (10 of 45) felt they needed more information and testing. There was a significant improvement in the level of decisional conflict, uncertainty, and perception of preparation for decision making for the caregivers between the first and second consult, although 60% of families did not complete the postconflict survey. CONCLUSIONS: The SDM process assists families in their need for more knowledge regarding risks, benefits, and options for treatment before making a surgical choice. SDM utilizing an impartial decision coach outside the direct circle of care and individualized epilepsy surgery education aids improves parental decision conflict and satisfaction.

How to combine rules and commitment in fostering research integrity?

Research integrity (RI) is crucial for trustworthy research. Rules are important in setting RI standards and improving research practice, but they can lead to increased bureaucracy; without commensurate commitment amongst researchers toward RI, they are unlikely to improve research practices. In this paper, we explore how to combine rules and commitment in fostering RI. Research institutions can govern RI using markets (using incentives), bureaucracies (using rules), and network processes (through commitment and agreements). Based on Habermas' Theory of Communicative Action, we argue that network processes, as part of the lifeworld, can legitimize systems - that is, market or bureaucratic governance modes. This can regulate and support RI practices in an efficient way. Systems can also become dominant and repress consensus processes. Fostering RI requires a balance between network, market and bureaucratic governance modes. We analyze the institutional response to a serious RI case to illustrate how network processes can be combined with bureaucratic rules. Specifically, we analyze how the Science Committee established at Tilburg University in 2012 has navigated different governance modes, resulting in a normatively grounded and efficient approach to fostering RI. Based on this case, we formulate recommendations to research institutions on how to combine rules and commitment.

Using co-creation methods for research integrity guideline development - how, what, why and when?

Existing research integrity (RI) guideline development methods are limited in including various perspectives. While co-creation methods could help to address this, there is little information available to researchers and practitioners on how, why and when to use co-creation for developing RI guidelines, nor what the outcomes of co-creation methods are. In this paper, we aim to address this gap. First, we discuss how co-creation methods can be used for RI guideline development, based on our experience of developing RI guidelines. We elaborate on steps including preparation of the aims and design; participant sensitization; organizing and facilitating workshops; and analyzing data and translating them into guidelines. Secondly, we present the resulting RI guidelines, to show what the outcome of co-creation methods are. Thirdly, we reflect on why and when researchers might want to use co-creation methods for developing RI guidelines. We discuss that stakeholder engagement and inclusion of diverse perspectives are key strengths of co-creation methods. We also reflect that co-creation methods have the potential to make guidelines implementable if followed by additional steps such as revision working groups. We conclude that co-creation methods are a valuable approach to creating new RI guidelines when used together with additional methods.

Toward a paradigm shift in healthcare: using the International Classification of Functioning, Disability and Health (ICF) and the capability approach (CA) jointly in theory and practice.

PURPOSE: Over the past two decades, healthcare systems have shifted to adopt a more holistic, patient-centered care system. However, operationalization in practice remains challenging. Two frameworks have contributed substantially to the transformation toward more holistic and patient-centered care: the International Classification of Functioning, Disability and Health (ICF) and the capability approach (CA). Using these frameworks jointly can contribute to improved patient-centered care in clinical practice. METHODS: This article explores the strengths and weaknesses of the use of the two frameworks in care and investigates whether using them jointly might contribute to more appropriate and patient-centered care. We will present a practical example of this integration in the form of a novel e-health application. RESULTS: The exploration indicated that if the frameworks are used jointly, the individual weaknesses can be overcome. The application, used to exemplify the joint use of the frameworks, contains all categories of the ICF. It offers a unique tool that allows a person to self-assess, record, and evaluate their functioning and capabilities and formulate related goals. CONCLUSIONS: Using the ICF jointly with the CA can foster holistic, patient-centered care. The e-health application provides a concrete example of how the frameworks can be used jointly. Implications for rehabilitationUsing the International Classification of Functioning, Disability and Health jointly with the capability approach can foster holistic, patient-centered care.The joint use of the frameworks is demonstrated by an e-health application which enables users to evaluate their functioning in relation to their own goals, provides them with the opportunity to increase control over their health and have a more active role in their care.Tools to record both functioning and goals from a patient's perspective can support professionals in offering patient-centered care in daily practice.Individual recording, monitoring and evaluation of functioning, capabilities and goals regarding functioning can provide a basis for research and quality improvement.

Moral values of Dutch physicians in relation to requests for euthanasia: a qualitative study.

BACKGROUND: In the Netherlands, patients have the legal right to make a request for euthanasia to their physician. However, it is not clear what it means in a moral sense for a physician to receive a request for euthanasia. The aim of this study is to explore the moral values of physicians regarding requests for euthanasia. METHODS: Semi-structured interviews were conducted with nine primary healthcare physicians involved in decision-making about euthanasia. The data were inductively analyzed which lead to the emergence of themes, one of which was about values regarding end-of-life decisions. RESULTS: Four clusters of values related to euthanasia requests are described: values related to 1) the patient; 2) the family; 3) the physician; and 4) life and death. The data show that the participants value patient autonomy as a necessary but not sufficient condition for meeting a euthanasia request. A good relationship with the patient and the family are important. For the physician, the values physician autonomy, responsibility, understanding the patient and relief of suffering play a role. Life as an intrinsic good and a peaceful death are also important values. CONCLUSION: This study shows that next to patient autonomy and the relationship with the patient and the family, it is important for the participants to act in accordance with their professional values and to do justice to values related to life and death. The awareness of going against the intrinsic value of life is crucial, even if performing euthanasia may result in a feeling of relief or gratitude afterwards.

A trial of intra-pleural bacterial immunotherapy in malignant pleural mesothelioma (TILT) - a randomised feasibility study using the trial within a cohort (TwiC) methodology.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive thoracic malignancy with a poor prognosis. Systemic immunotherapy is an effective frontline treatment for MPM, and there is a scientific rationale supporting the possible efficacy of local, i.e. intra-pleural immune modulators. Trial of intra-pleural bacterial immunotherapy (TILT) investigated the feasibility of performing a randomised trial of intra-pleural bacterial immunotherapy in people with MPM, using the trials within cohorts (TwiC) methodology. METHODS: TILT was a multicentre, three-armed, randomised, feasibility TwiC of intra-pleural OK432, BCG, or usual care in people with MPM. Eligible participants were identified from within the ASSESS-meso study, a prospective, longitudinal, observational cohort study, and were randomly selected to be offered a single dose of OK432 or BCG, via an indwelling pleural catheter. The primary outcome was feasibility, evaluated against prespecified recruitment, attrition and data completeness targets. The acceptability of trial processes and interventions was assessed during qualitative interviews with participants and family members at the end of the trial. TILT was registered prospectively on the European Clinical Trials Registry (EudraCT number 2016-004,727-23) and the ISRCTN Register on 04 December 2017. RESULTS: Seven participants were randomised from a planned sample size of 12; thus, the 66% recruitment rate target was not met. Two participants withdrew after randomisation, breaching the pre-stated attrition threshold of 10%. It was not possible to maintain blinding of control participants, which negated a fundamental tenet of the TwiC design. The trial processes and methodology were generally acceptable to participants and relatives, despite several recipients of intra-pleural bacterial agents experiencing significant local and systemic inflammatory responses. CONCLUSION: It was possible to design a clinical trial of an investigational medicinal product based on the TwiC design and to obtain the necessary regulatory approvals. However, whilst acceptable to participants and relatives, the TwiC design was not a feasible method of investigating intra-pleural bacterial immunotherapy in people with MPM. Future trials investigating this topic should consider the eligibility constraints and recruitment difficulties encountered. TRIAL REGISTRATION: TILT was registered prospectively on the European Clinical Trials Registry (EudraCT number 2016-004727-23 ) and the ISRCTN Register ( 10432197 ) on 04 December 2017.

Stakeholders' Experiences of Research Integrity Support in Universities: A Qualitative Study in Three European Countries.

Fostering research integrity (RI) increasingly focuses on normative guidance and supportive measures within institutions. To be successful, the implementation of support should be informed by stakeholders' experiences of RI support. This study aims to explore experiences of RI support in Dutch, Spanish and Croatian universities. In total, 59 stakeholders (Netherlands n = 25, Spain n = 17, Croatia n = 17) participated in 16 focus groups in three European countries. Global themes on RI support experiences were identified by thematic analysis. Themes identified were: 'RI governance and institutional implementation', 'RI roles and structures', 'RI education and supervision', and 'Infrastructure, technology and tools supporting daily practice'. Experiences of support differed between countries in relation to: the efforts to translate norms into practice; the extent to which RI oversight was a responsibility of RE structures, or separate RI structures; and the availability of support close to research practice, such as training, responsible supervision, and adequate tools and infrastructure. The study reinforces the importance of a whole institutional approach to RI, embedded within local jurisdictions, rules, and practices. A whole institutional approach puts the emphasis of responsibility on institutions rather than individual researchers. When such an approach is lacking, some stakeholders look for intervention by authorities, such as funders, outside of the university.

How can research institutions support responsible supervision and leadership?

Supervisors, PhD candidates and research leaders are expected to be the primary persons responsible for maintaining a high research integrity standards. However, research institutions should support them in this effort, by promoting responsible supervision and leadership practices. Although it is clear that institutions play a crucial role in this, there is a lack of institutional guidelines focusing on these topics. The development of the experience-based guidelines presented in this article consisted of a multi-step, iterative approach. We engaged 16 experts in supervision and research integrity in four workshops to co-create institutional guidelines for responsible supervision and leadership. To revise the guidelines and make them operational, we formed a dedicated working group and consulted experts in the field of supervision. This resulted in three guidelines focusing on what institutions can do to support: responsible supervision, PhD candidates during their PhD trajectory, and responsible leadership. The recommendations focus on the rights and responsibilities of the three targeted stakeholder groups, and institutions' responsibilities for the personal development and well-being of supervisors, PhD candidates and research leaders. The three guidelines can be used by institutions to foster responsible supervision and leadership by supporting researchers to conduct research with integrity.

BigMove: A Group Intervention for People with Physical and Mental Health Conditions: Development, Theoretical Frameworks, Essential Elements and Design.

Introduction: This article describes an innovative, integrated care intervention, called BigMove, which aims to improve the functioning, capabilities and quality of life of people with a combination of physical and mental health conditions. Description: Theoretical frameworks reflected in the intervention are the Capability Approach (CA) and Self-Determination Theory (SDT). Essential elements of the intervention included to expand participants' behavioural repertoire are motivational interviewing; functional goal setting (using the International Classification of Functioning, Disability and Health (ICF); cognitive behavioural therapy; enjoyment; support of the group; and physical activity. The design combines individual sessions and group sessions. Discussion: By integrating the CA and the SDT, the intervention enables participants to make self-directed and value-driven choices in life and change their behaviour accordingly to strengthen their functioning and capabilities. To foster person-centred, integrated care, it is crucial to reform the interaction between professionals and patients and to re-structure the organisation and financing of care to enable the provision of complex integrated care interventions. Conclusion: For people with physical and mental health conditions, the intervention BigMove provides an innovative integrated care approach that addresses aspirations people have regarding their functioning and focuses on individual goal setting and behaviour change.

Development and Testing of the Curiosity in Classrooms Framework and Coding Protocol.

Curiosity is widely acknowledged as a crucial aspect of children's development and as an important part of the learning process, with prior research showing associations between curiosity and achievement. Despite this evidence, there is little research on the development of curiosity or on promoting curiosity in school settings, and measures of curiosity promotion in the classroom are absent from the published literature. This article introduces the Curiosity in Classrooms (CiC) Framework coding protocol, a tool for observing and coding instructional practices that support the promotion of curiosity. We describe the development of the framework and observation instrument and the results of a feasibility study using the protocol, which gives a descriptive overview of curiosity-promoting instruction in 35 elementary-level math lessons. Our discussion includes lessons learned from this work and suggestions for future research using the developed observation tool.

Manifestations of circulatory assist devices in noninvasive arterial duplex evaluation: A pictorial review.

Spectral Doppler and plethysmographic waveforms vary significantly in the presence of circulatory assist devices. Understanding the effect these devices have on the waveforms and flow characteristics is necessary for the appropriate interpretation of duplex ultrasound and other noninvasive vascular studies. We review the different arterial waveforms that can be seen with circulatory assist devices.

Irremediable Psychiatric Suffering in The Context of Medical Assistance in Dying: A Delphi-Study.

OBJECTIVE: Patients with a psychiatric disorder are eligible to request medical assistance in dying (MAID) in a small but growing number of jurisdictions, including the Netherlands and Belgium. In Canada, MAID for mental illness will become possible in 2023. For this request to be granted, most of these jurisdictions demand that the patient is competent in her request, and that the suffering experienced is unbearable and irremediable. Especially the criterion of irremediability is challenging to establish in patients with psychiatric disorders. The aim of this research is to establish what criteria Dutch and Belgian experts agree to be necessary in characterising irremediable psychiatric suffering (IPS) in the context of MAID. METHODS: A two-round Delphi procedure among psychiatrists with relevant experience. RESULTS: Thirteen consensus criteria were established: five diagnostic and eight treatment-related criteria. Diagnostically, the participants deem a narrative description and attention to contextual and systemic factors necessary. Also, a mandatory second opinion is required. The criteria concerning treatment show that extensive biopsychosocial treatment is needed, and the suffering must be present for several years. Finally, in the case of refusal, the participants agree that there are limits to the number of diagnostic procedures or treatments a patient must undergo. CONCLUSIONS: Consensus was found among a Dutch and Belgian expert group on potential criteria for establishing IPS in the context of MAID. These criteria can be used in clinical decision-making and can inform future procedural demands and research.