Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy.

Importance: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown. Objective: To test the association between pathogenic somatic variants in the hippocampus and MTLE. Design, Setting, and Participants: This case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy-associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022. Exposures: Drug-resistant MTLE. Main Outcomes and Measures: Presence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex. Results: Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9]; P = .01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11, SOS1, KRAS, BRAF, and NF1, all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism. Conclusions and Relevance: Hippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery.

How the past influences interprofessional collaboration between obstetricians and midwives in the Netherlands: Findings from a secondary analysis.

Collaborations between groups of professionals often have a long history, which can still influence contemporary practice. If problems in the collaboration occur, the search for effective interventions for these problems may be informed by analysing current practice as well as the historical development of the collaboration. The study focused on the collaboration between obstetricians and midwives in the Netherlands. We performed a secondary analysis of questionnaire data focusing on midwives evaluating the collaborative performance of obstetricians in the Netherlands. Template analysis was used to analyse the questionnaires. The initial template was based on a model for interprofessional collaboration. As a final step, we reflected on the results in light of the historical development of the collaboration. The midwives experienced a power imbalance and a lack of trust and mutual acquaintanceship in their collaboration with obstetricians. They also reported a need for interprofessional governance and formalization. Most of these reported problems in the collaboration have their origin in the historical development of both professions and in the development of the collaboration between both professional groups. Combining an exploration of contemporary interprofessional practice with a historical perspective on interprofessional collaboration is fruitful for understanding problems in collaboration between professional groups, and provides guidance for improving collaboration.

Factors influencing intercultural doctor-patient communication: a realist review.

OBJECTIVE: Due to migration, doctors see patients from different ethnic backgrounds. This causes challenges for the communication. To develop training programs for doctors in intercultural communication (ICC), it is important to know which barriers and facilitators determine the quality of ICC. This study aimed to provide an overview of the literature and to explore how ICC works. METHODS: A systematic search was performed to find literature published before October 2012. The search terms used were cultural, communication, healthcare worker. A realist synthesis allowed us to use an explanatory focus to understand the interplay of communication. RESULTS: In total, 145 articles met the inclusion criteria. We found ICC challenges due to language, cultural and social differences, and doctors' assumptions. The mechanisms were described as factors influencing the process of ICC and divided into objectives, core skills and specific skills. The results were synthesized in a framework for the development of training. CONCLUSION: The quality of ICC is influenced by the context and by the mechanisms. These mechanisms translate into practical points for training, which seem to have similarities with patient-centered communication. PRACTICE IMPLICATIONS: Training for improving ICC can be developed as an extension of the existing training for patient-centered communication.

An examination of the historical context of interprofessional collaboration in Dutch obstetrical care.

Collaboration between different groups of health care professionals is often rooted in a long and often difficult history. This history can exert a strong influence on how professionals collaborate and historical tensions can contribute to problems in contemporary practice. However, literature about interprofessional collaboration often ignores the historical underpinnings of collaboration. In this paper, the historical development of interprofessional collaboration between obstetricians and midwives within the setting of Dutch obstetrical care is explored using a review of Dutch and English literature for documents explicitly or implicitly describing the historical development of this collaboration. This literature delineates the establishment of professional boundaries and the formalization of the collaboration between the two professions. It also details the history of physician domination over the midwives both in midwifery practice and education and the relatively recent reversal of this situation. Moreover, the shift in collaborative partner from general practitioner to obstetrician and its effect on collaboration is examined. Insight into the historical foundations of Dutch maternity care collaboration may allow us to understand the origins, and thus formulate possible solutions, for contemporary problems within this collaboration.

The CanMEDS framework: relevant but not quite the whole story.

BACKGROUND: Despite acknowledgement that the Canadian Medical Educational Directives for Specialists (CanMEDS) framework covers the relevant competencies of physicians, many educators and medical professionals struggle to translate the CanMEDS roles into comprehensive training programmes for specific specialties. AIM: To gain insight into the applicability of the CanMEDS framework to guide the design of educational programmes for specific specialties by exploring stakeholders' perceptions of specialty specific competencies and examining differences between those competencies and the CanMEDS framework. METHODS: This case study is a sequel to a study among ObsGyn specialists. It explores the perspectives of patients, midwives, nurses, general practitioners, and hospital boards on gynaecological competencies and compares these with the CanMEDS framework. RESULTS: Clinical expertise, reflective practice, collaboration, a holistic view, and involvement in practice management were perceived to be important competencies for gynaecological practice. Although all the competencies were covered by the CanMEDS framework, there were some mismatches between stakeholders' perceptions of the importance of some competencies and their position in the framework. CONCLUSION: The CanMEDS framework appears to offer relevant building blocks for specialty specific postgraduate training, which should be combined with the results of an exploration of specialty specific competencies to arrive at a postgraduate curriculum that is in alignment with professional practice.

Exploration of perceived effects of innovations in postgraduate medical education.

CONTEXT: Many studies have examined how educational innovations in postgraduate medical education (PGME) impact on teaching and learning, but little is known about effects in the clinical workplace outside the strictly education-related domain. Insights into the full scope of effects may facilitate the implementation and acceptance of innovations because expectations can be made more realistic, and difficulties and pitfalls anticipated. Using workplace-based assessment (WBA) as a reference case, this study aimed to determine which types of effect are perceived by users of innovations in PGME. METHODS: Focusing on WBA as a recent instance of innovation in PGME, we conducted semi-structured interviews to explore perceptions of the effects of WBA in a purposive sample of Dutch trainees and (lead) consultants in surgical and non-surgical specialties. Interviews conducted in 2011 with 17 participants were analysed thematically using template analysis. To support the exploration of effects outside the domain of education, the study design was informed by theory on the diffusion of innovations. RESULTS: Six domains of effects of WBA were identified: sentiments (affinity with the innovation and emotions); dealing with the innovation; specialty training; teaching and learning; workload and tasks, and patient care. Users' affinity with WBA partly determined its effects on teaching and learning. Organisational support and the match between the innovation and routine practice were considered important to minimise additional workload and ensure that WBA was used for relevant rather than easily assessable training activities. Dealing with WBA stimulated attention for specialty training and placed specialty training on the agenda of clinical departments. CONCLUSIONS: These outcomes are in line with theoretical notions regarding innovations in general and may be helpful in the implementation of other innovations in PGME. Given the substantial effects of innovations outside the strictly education-related domain, individuals designing and implementing innovations should consider all potential effects, including those identified in this study.

Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that remains difficult to treat. Even with current standard HLH therapy, only approximately half of patients will experience complete resolution of disease, and early mortality remains a significant problem. Salvage therapies have been described only in limited case reports, and there are no large studies of second-line therapies. PROCEDURE: We reviewed the charts of 22 pediatric and adult patients who received alemtuzumab for the treatment of refractory HLH at our center or in consultation with our group. RESULTS: Patients had received conventional therapies for a median of 8 weeks (range: 2-70) prior to alemtuzumab, and treatment immediately prior to alemtuzumab included dexamethasone (100%), etoposide (77%), cyclosporine (36%), intrathecal hydrocortisone ± methotrexate (23%), methylprednisolone (9%), and rituximab (14%). Patients received a median dose of 1 mg/kg alemtuzumab (range: 0.1-8.9 mg/kg) divided over a median of 4 days (range: 2-10). Fourteen patients experienced an overall partial response, defined as at least a 25% improvement in two or more quantifiable symptoms or laboratory markers of HLH 2 weeks following alemtuzumab (64%). Five additional patients had a 25% or greater improvement in a single quantifiable symptom or laboratory marker of HLH (23%). Seventy-seven percent of patients survived to undergo allogeneic hematopoietic cell transplantation. Patients experienced an acceptable spectrum of complications, including CMV and adenovirus viremia. CONCLUSION: Alemtuzumab appears to be an effective salvage agent for refractory HLH, leading to improvement and survival to HCT in many patients. Prospective trials to define optimal dosing levels, schedules, and responses are needed.

How lead consultants approach educational change in postgraduate medical education.

CONTEXT: Consultants in charge of postgraduate medical education (PGME) in hospital departments ('lead consultants') are responsible for the implementation of educational change. Although difficulties in innovating in medical education are described in the literature, little is known about how lead consultants approach educational change. OBJECTIVES: This study was conducted to explore lead consultants' approaches to educational change in specialty training and factors influencing these approaches. METHODS: From an interpretative constructivist perspective, we conducted a qualitative exploratory study using semi-structured interviews with a purposive sample of 16 lead consultants in the Netherlands between August 2010 and February 2011. The study design was based on the research questions and notions from corporate business and social psychology about the roles of change managers. Interview transcripts were analysed thematically using template analysis. RESULTS: The lead consultants described change processes with different stages, including cause, development of content, and the execution and evaluation of change, and used individual change strategies consisting of elements such as ideas, intentions and behaviour. Communication is necessary to the forming of a strategy and the implementation of change, but the nature of communication is influenced by the strategy in use. Lead consultants differed in their degree of awareness of the strategies they used. Factors influencing approaches to change were: knowledge, ideas and beliefs about change; level of reflection; task interpretation; personal style, and department culture. CONCLUSIONS: Most lead consultants showed limited awareness of their own approaches to change. This can lead them to adopt a rigid approach, whereas the ability to adapt strategies to circumstances is considered important to effective change management. Interventions and research should be aimed at enhancing the awareness of lead consultants of approaches to change in PGME.

The curriculum for the doctor of the future: messages from the clinician's perspective.

BACKGROUND: Medical curricula should focus on the future of health care. Contemporary competency frameworks for curriculum design such as Canadian Medical Education Directions for Specialists (CanMEDS), ACGME and Tomorrow's Doctors share this vision by stressing generic competencies. AIM: The objective of this study was to investigate how well a contemporary competency framework fits in with clinicians' perspectives on future health care. METHODS: Using a strategic planning approach, a semi-structured open-ended questionnaire on the future of their profession was sent to 102 Dutch gynecologists. Through inductive analysis, a future perspective and its needed competencies were identified and compared to the CanMEDS framework. RESULTS: The 62 responses showed content validity for the CanMEDS roles. Additionally, two roles were identified: advanced technology user and entrepreneur. Within the role Communicator, the focus will change through more active patient participation. The roles Collaborator and Manager are predicted to change in focus because of an increase of complex interdisciplinary teamwork and leadership roles. CONCLUSION: By studying the Dutch gynecologists' perspective of the future in a strategic planning approach, two additional roles and focus areas within a contemporary competency framework were identified. The perspective of clinicians on future health care provides valuable messages on how to design future-proof curricula.

Changes in cytokine production and composition of peripheral blood leukocytes during pregnancy are not associated with a difference in the proliferative immune response to the fetus.

We analyzed peripheral blood from women at term pregnancy for leukocyte composition, in vitro proliferative responses and cytokine production after nonspecific and fetus-specific stimulation. Maternal peripheral blood mononuclear cells (PBMCs) were collected and stimulated with umbilical cord blood (UCB) of the mother's own child, third-party UCB, nonspecific stimulus phytohemagglutinin, and anti-CD3 antibody, with PBMCs of nonpregnant women (cPBMC) as controls. Nine combinations of patient, child, third party child, and controls were selected on basis of sharing one human leukocyte antigen (HLA)-DR antigen. The response of mPBMC upon specific stimulation with fetal antigens was similar to that of cPBMC. No differences were found when comparing the mother's response upon stimulation to her own child with stimulation to that with a control child. Nonspecific stimulation with phytohemagglutinin and anti-CD3 antibody did not reveal a difference in proliferation rate between mPBMC and cPBMC. However, mPBMC contained a higher percentage of CD14(+) cells (p = 0.001) and activated T cells (CD25(dim), p < 0.0001), but a lower percentage CD16(-)CD56(bright) natural killer (NK) cells (p = 0.001) and CD16(+)CD56(+) NK cells (p = 0.003). mPBMC produced more interleukin (IL)-6, IL-10, and IL-17 compared with cPBMC (p < 0.05). We found differences in lymphocyte composition and cytokine production between mPBMC and cPBMC. These differences did not result in quantitative changes in proliferative responses during pregnancy compared with responses in nonpregnant controls.

Understanding the transition from resident to attending physician: a transdisciplinary, qualitative study.

PURPOSE: There is a paucity of research into the processes surrounding the transition from residency to the position of attending physician. This report retrospectively investigates the question: Are attending physicians adequately prepared and trained to perform the tasks and duties of their new position? This study aimed at formulating a conceptual framework that captures the transition and is applicable beyond discipline- or location-specific boundaries. METHOD: Individual semistructured interviews were conducted and analyzed using a qualitative, grounded theory approach. Between January and May 2009, 14 physicians were interviewed who had commenced an attending post in internal medicine or obstetrics-gynecology between six months and two years earlier, within the Netherlands. Interviews focused on the attendings' perceptions of the transition, their socialization within the new organization, and the preparation they had received during residency training. The interview transcripts were openly coded, and through constant comparison, themes emerged. The research team discussed the results until full agreement was reached. RESULTS: A conceptual framework emerged from the data, consisting of three themes interacting in a longitudinal process. The framework describes how novel disruptive elements (first theme) due to the transition from resident to attending physician are perceived and acted on (second theme), and how this directs new attendings' personal development (third theme). CONCLUSIONS: The conceptual framework finds support in transition psychology and notions from organizational socialization literature. It provides insight into the transition from resident to attending physician that can inform measures to smooth the intense transition.

False-positive metaiodobenzylguanidine scan for neuroblastoma in a child with opsoclonus-myoclonus syndrome treated with adrenocorticotropic hormone (acth).

We describe the case of a 2-year-old girl with opsoclonus-myoclonus syndrome treated with chronic adrenocorticotropic hormone (ACTH) in which a metaiodobenzylguanidine scan showed abnormal radiotracer uptake in the left adrenal gland region, interpreted as the site of an occult neuroblastoma. As this finding was not corroborated by previous or subsequent metaiodobenzylguanidine scans or by computed tomography (CT) or magnetic resonance imaging (MRI), we attribute the finding to being a false-positive result from adrenal hyperplasia owing to chronic use of ACTH and not to neuroblastoma. Metaiodobenzylguanidine scintigraphy is an extremely important nuclear medicine examination tool used for the evaluation and staging of pediatric neuroblastoma. We highlight the need for cautious interpretation of metaiodobenzylguanidine as a screening tool for neuroblastoma in patients treated with ACTH.

Immunophenotype of blood lymphocytes in neuroblastoma-associated opsoclonus-myoclonus.

OBJECTIVE: To determine whether the distribution of peripheral blood mononuclear cells (PBMCs) is altered in paraneoplastic opsoclonus-myoclonus (POM). METHODS: PBMCs from 17 children with POM, 17 children with OM but no tumor, and 17 controls were immunophenotyped using a comprehensive panel of surface markers by dual-laser flow cytometry. All groups were matched for age and gender; POM and OM patients were matched for treatment. RESULTS: In the POM patients, the CD4+ T-cell subset was smaller in both relative size (-18%, P = 0.02) and absolute size (-41%, P = 0.03) compared with controls. The CD4/CD8 ratio also was less (-29% to -44%) and was related to POM duration (P = 0.03). The absolute but not relative size of the gammadelta T-cell subset was reduced (-44%, P = 0.02). There were no significant abnormalities of CD19+ B-cells, CD3- or CD3+ NK cells, HLA-DR+ or CD25+ T-cells, or CD45RA+ or CD45RO+ T-cells. Prior tumor chemotherapy, which was associated with a higher percentage but not number of CD8+ T-cells, did not restore the CD4+ T-cell subset. When the POM and OM groups, which were not significantly different, were combined, chemotherapy decreased both the relative and absolute size of the CD19+ B-cell pool and had small effects on other lymphocyte subsets. CONCLUSIONS: POM is characterized by T-cell abnormalities of PBMCs, the most robust of which is reduction of the CD4+ T-cell subset and the CD4/CD8 ratio. Although this reduction was found previously in cerebrospinal fluid in POM patients, PBMC subsets did not otherwise reflect cerebrospinal fluid abnormalities. Longitudinal studies will be necessary to determine whether PBMC abnormalities could serve as treatment markers.