Improving patient self-reporting of antihypertensive adverse drug events in primary care: a stepped wedge cluster randomised trial.

BACKGROUND: About 25% of patients experience adverse drug events (ADE) in primary care, but few events are reported by the patients themselves. One solution to improve the detection and management of ADEs in primary care is for patients to report them to their general practitioner. The study aimed to assess the effect of a booklet designed to improve communication and interaction between patients treated with anti-hypertensive drugs and general practitioners on the reporting of ADEs. METHODS: A cluster randomized controlled cross-sectional stepped wedge open trial (five periods of 3 months) was conducted. A cluster was a group of general practitioners working in ambulatory offices in France. Adults consulting their general practitioner to initiate, modify, or renew an antihypertensive prescription were included. A booklet including information on cardiovascular risks, antihypertensive treatments, and ADE report forms was delivered by the general practitioner to the patient in the intervention group. The primary outcome was the reporting of at least one ADE by the patient to his general practitioner during the three-month period after enrolment. Two clusters were randomised by sequence for a total of 8 to receive the intervention. An intention-to-treat analysis was conducted. A logistic mixed model with random intercept was used. RESULTS: Sixty general practitioners included 1095 patients (median: 14 per general practitioner; range: 1-103). More patients reported at least one ADE to their general practitioner in the intervention condition compared to the control condition (aOR = 3.5, IC95 [1.2-10.1], p = 0.02). The modification and initiation of an antihypertensive treatment were also significantly associated with the reporting of ADEs (aOR = 4.4, CI95 [1.9-10.0], p <  0.001 and aOR = 11.0, CI95 [4.6-26.4], p <  0.001, respectively). The booklet delivery also improved patient satisfaction on general practitioner communication and high blood pressure management. CONCLUSION: A booklet can improve patient self-reporting of ADEs to their general practitioners. Future research should assess whether it can improve general practitioner management of ADEs and patient's health status. TRIAL REGISTRATION: Trial registry identifier NCT01610817 (2012/05/30).

Un médiateur dans un service d'urgences hospitalières : quelles missions selon les personnels ?

OBJECTIVES: Violence in emergency services has become a central issue in the daily work of hospital employees. While the use of video surveillance and the training of professionals in conflict management are the most common methods used, there are few cases using the setting up of a third part such as a mediator. We conducted a qualitative study with professionals to examine their representations associated with mediation. METHOD: Semi-directive interviews were conducted with professionals from four emergency units. The topics discussed in interviews were the definition of mediation and the missions that the mediators should fulfil. The content of 38 semi-directive interviews was analysed according to the inductive approach of the grounded theory. A content analysis was made, followed by an analysis aiming to bring out types and convergences/divergences. RESULTS: Professionals were not aware of the definition of mediation and of its missions. They linked to it an instrumental theme, making mediation a tool for conflict prevention and management, a tool for communication with patients about their care, and about the organisation of emergency unit. The upcoming presence of mediators was seen as an help. A potential competition between professionals and mediators in the tasks performed was identified. CONCLUSION: The study shows a favourable opinion towards mediation. It has allowed to identify obstacles to the well-functioning of the missions assigned to mediators. One of the challenges is the integration of this new actor, the mediator.

[Mediators in emergency services: what missions according to the staff?] / Un médiateur dans un service d'urgences hospitalières : quelles missions selon les personnels ?

OBJECTIVES: Violence in emergency services has become a central issue in the daily work of hospital employees. While the use of video surveillance and the training of professionals in conflict management are the most common methods used, there are few cases using the setting up of a third part such as a mediator. We conducted a qualitative study with professionals to examine their representations associated with mediation. METHOD: Semi-directive interviews were conducted with professionals from four emergency units. The topics discussed in interviews were the definition of mediation and the missions that the mediators should fulfil. The content of 38 semi-directive interviews was analysed according to the inductive approach of the grounded theory. A content analysis was made, followed by an analysis aiming to bring out types and convergences/divergences. RESULTS: Professionals were not aware of the definition of mediation and of its missions. They linked to it an instrumental theme, making mediation a tool for conflict prevention and management, a tool for communication with patients about their care, and about the organisation of emergency unit. The upcoming presence of mediators was seen as an help. A potential competition between professionals and mediators in the tasks performed was identified. CONCLUSION: The study shows a favourable opinion towards mediation. It has allowed to identify obstacles to the well-functioning of the missions assigned to mediators. One of the challenges is the integration of this new actor, the mediator.

[Emergence of the patient-actor in patient safety in France. A narrative review in social sciences and public health]. / L'émergence du patient-acteur dans la sécurité des soins en France : une revue narrative de la littérature entre sciences sociales et santé publique.

INTRODUCTION: For the last forty years, patients have been encouraged to take part in their care and to participate in improving the quality and safety of care. This phenomenon requires reflection on the conditions of emergence of this new role and its public health implications, particularly in the field of patient safety. METHODS: A narrative review of the international literature was conducted by searching Medline, Cairn and Persée databases. RESULTS: The database query identified 2,206 documents, 106 of which were included in the analysis. The emergence of the patient-actor is linked to sanitary crises and promoted by patient associations in the field of patient safety such as le Lien. This movement induces a transformation of the patient's role beyond the theme of patient safety: it revolutionizes the patient's contribution to the health system. CONCLUSION: This narrative review of the literature highlights the way in which health crises have encouraged the emergence of a new actor: the patient-actor, accompanied by new semantics concerning the power of the patient. The patient occupies a specific place in the field of safety of care. In collaboration with healthcare professionals, the patient must constitute a resource to improve patient safety. The various contributions of patients are described and an analysis of the acceptability of patient participation is proposed.

LKB1 signaling in cephalic neural crest cells is essential for vertebrate head development.

Head development in vertebrates proceeds through a series of elaborate patterning mechanisms and cell-cell interactions involving cephalic neural crest cells (CNCC). These cells undergo extensive migration along stereotypical paths after their separation from the dorsal margins of the neural tube and they give rise to most of the craniofacial skeleton. Here, we report that the silencing of the LKB1 tumor suppressor affects the delamination of pre-migratory CNCC from the neural primordium as well as their polarization and survival, thus resulting in severe facial and brain defects. We further show that LKB1-mediated effects on the development of CNCC involve the sequential activation of the AMP-activated protein kinase (AMPK), the Rho-dependent kinase (ROCK) and the actin-based motor protein myosin II. Collectively, these results establish that the complex morphogenetic processes governing head formation critically depends on the activation of the LKB1 signaling network in CNCC.

The RNA-binding protein Mex3b regulates the spatial organization of the Rap1 pathway.

The four related mammalian MEX-3 RNA-binding proteins are evolutionarily conserved molecules for which the in vivo functions have not yet been fully characterized. Here, we report that male mice deficient for the gene encoding Mex3b are subfertile. Seminiferous tubules of Mex3b-deficient mice are obstructed as a consequence of the disrupted phagocytic capacity of somatic Sertoli cells. In addition, both the formation and the integrity of the blood-testis barrier are compromised owing to mislocalization of N-cadherin and connexin 43 at the surface of Sertoli cells. We further establish that Mex3b acts to regulate the cortical level of activated Rap1, a small G protein controlling phagocytosis and cell-cell interaction, through the activation and transport of Rap1GAP. The active form of Rap1 (Rap1-GTP) is abnormally increased at the membrane cortex and chemically restoring Rap1-GTP to physiological levels rescues the phagocytic and adhesion abilities of Sertoli cells. Overall, these findings implicate Mex3b in the spatial organization of the Rap1 pathway that orchestrates Sertoli cell functions.

[The emergence of patient safety issues in France]. / L'émergence de la question de la sécurité des patients en France.

INTRODUCTION: The objective of this study was to elucidate the conditions of emergence of patient safety issues in the public debate and the limits to implementation of patient safety in the current health system. METHOD: A narrative review of the international literature was conducted by searching PubMed, Cairn and Persée databases. RESULTS: The database search retrieved 2,206 documents, 48 of which were included in the study. The theme of patient safety has spread worldwide, but emerged late in France. The delayed emergence of patient safety in France is essentially related to the euphemistic approach to the problem of patient safety, the difficulty of adopting systematic reasoning, the lack of human resources management levers and the ambiguous position of patients in relation to patient safety.

The RNA-binding E3 ubiquitin ligase MEX-3C links ubiquitination with MHC-I mRNA degradation.

RNA-binding E3 ubiquitin ligases were recently identified, though their function remains unclear. While studying the regulation of the MHC class I (MHC-I) pathway, we here characterize a novel role for ubiquitin in mRNA degradation. MHC-I molecules provide ligands for both cytotoxic T-lymphocytes as well as natural killer (NK) cells, and play a central role in innate and adaptive immunity. MHC-I cell-surface expression is closely monitored by NK cells, whose killer immunoglobulin-like receptors encode MHC-I-specific activatory and inhibitory receptors, implying that MHC-I expression needs to be tightly regulated. In a functional siRNA ubiquitome screen we identified MEX-3C, a novel RNA-binding ubiquitin E3 ligase, as responsible for the post-transcriptional, allotype-specific regulation of MHC-I. MEX-3C binds the 3'UTR of HLA-A2 mRNA, inducing its RING-dependent degradation. The RING domain of MEX-3C is not required for HLA-A2 cell-surface downregulation, but regulates the degradation of HLA-A2 mRNA. We have therefore uncovered a novel post-transcriptional pathway for regulation of HLA-A allotypes and provide a link between ubiquitination and mRNA degradation.

A multifaceted risk management program to improve the reporting rate of patient safety incidents in primary care: a cluster-randomised controlled trial.

BACKGROUND: While patient safety incident reporting is of key importance for patient safety in primary care, the reporting rate by healthcare professionals remains low. This study aimed to assess the effectiveness of a risk management program in increasing the reporting rate within multiprofessional primary care facilities. METHODS: A nation-wide cluster-randomised controlled trial was performed in France, with each cluster defined as a primary care facility. The intervention included professional e-learning training, identification of a risk management advisor, and multidisciplinary meetings to address incident analysis. In the first observational period, a patient safety incident reporting system for professionals was implemented in all facilities. Then, facilities were randomised, and the program was implemented. Incidents were reported over the 15-month study period. Quasi-Poisson models were used to compare reporting rates. RESULTS: Thirty-five facilities (intervention, n = 17; control, n = 18) were included, with 169 and 232 healthcare professionals, respectively, involved. Overall, 7 out of 17 facilities carried out the entire program (41.2%), while 6 did not hold meetings (35.3%); 48.5% of professionals logged on to the e-learning website. The relative rate of incidents reported was 2.7 (95% CI = [0.84-11.0]; p = 0.12). However, a statistically significant decrease in the incident rate between the pre-intervention and post-intervention periods was observed for the control arm (HR = 0.2; 95% CI = [0.05-0.54]; p = 0.02), but not for the intervention arm (HR = 0.54; 95% CI = [0.2-1.54]; p = 0.23). CONCLUSION: This program didn't lead to a significant improvement in the patient safety incident reporting rate by professionals but seemed to sustain reporting over time. Considering that the program was fully implemented in only 41% of facilities, this highlights the difficulty of implementing such multidisciplinary programs in primary care despite its adaptation to the setting. A better understanding of how risk management is currently organized in these multiprofessional facilities is of key importance to improve patient safety in primary care. TRIAL REGISTRATIONS: The study has been registered at clinicaltrials.gov (NCT02403388) on 30 March 2015.

Impact of the presence of a mediator on patient violent or uncivil behaviours in emergency departments: a cluster randomised crossover trial.

BACKGROUND AND IMPORTANCE: Several studies reported that violent behaviours were committed by patients against healthcare professionals in emergency departments (EDs). The presence of mediators could prevent or resolve situations of tension. OBJECTIVE: To evaluate whether the presence of mediators in EDs would have an impact on violent behaviours committed by patients or their relatives against healthcare professionals. Design, settings and participants A 6-period cluster randomised crossover trial was performed in 4 EDs during 12 months. Patients aged ≥18 and their relatives were included. INTERVENTION: In order to prevent or resolve situations of tension and conflict, four mediators were recruited.Outcome measure and analysis Using a logistic regression mixed model, the rate of ED visits in which at least one act of violence was committed by a patient or their relatives, reported by healthcare professionals, was compared between the intervention group and the control group. RESULTS: A total of 50 429 ED visits were performed in the mediator intervention group and 50 851 in the control group. The mediators reported 1365 interventions; >50% of the interventions were to answer questions about clinical management or waiting time. In the intervention group, 173 acts of violence were committed during 129 ED visits, and there were 145 acts of violence committed during 106 ED visits in the control group. The rate of ED visits in which at least one act of violence was committed, was 0.26% in the intervention group and 0.21% in the control group (OR = 1.23; 95% CI [0.73-2.09]); on a 4-level seriousness scale, 41.6% of the acts of violence were rated level-1 (acts of incivility or rudeness) in the intervention group and 40.0% in the control group. CONCLUSION: The presence of mediators in the ED was not associated with a reduction in violent or uncivil behaviours committed by patients or their relatives. However, the study highlighted that patients had a major need for information regarding their care; improving communication between patients and healthcare professionals might reduce the violence in EDs. TRIAL REGISTRATION: Clinicaltrials.gov (NCT03139110).

[Information and active patient participation using an interactive booklet in the prescription of antihypertensive drugs in primary care]. / Information et participation active des patients à l'aide d'une brochure interactive lors de la prescription d'antihypertenseurs en soins primaires.

AIM: Antihypertensive drugs are thought to be responsible for adverse drug events in 25% of patients, with severe consequences in 13% of cases. The purpose of this study was to develop an interactive booklet designed to inform and involve patients with a view to preventing adverse drug events. METHODS: The development of the booklet involved several stages, including a literature review, a Delphi survey, a readability assessment, a qualitative study in primary care, a revision process, and graphic design work. 27 experts (patients, general practitioners, public health practitioners, cardiologists, geriatricians, psychologists, economists, pharmacists, nurses and ethicists) participated in the Delphi survey, while the qualitative study was based on a sample that included 7 doctors, 13 patients and 2 healthcare assistants. RESULTS: We developed an interactive booklet containing information items on the benefits and risks of antihypertensive drugs, a care plan to be completed by the patient, and a form for reporting adverse drug events. Ambiguous sentences and incomprehensible medical terms were rephrased. The time required to present the booklet and ease of use were key acceptability criteria for caregivers. Among the patients, the study found that interest in the booklet required clear evidence of an expected benefit. CONCLUSION: An understandable and acceptable interactive booklet was developed using a systematic process to prevent severe adverse drug events in primary care.

Feelings of Trust and of Safety Are Related Facets of the Patient's Experience in Surgery: A Descriptive Qualitative Study in 80 Patients.

OBJECTIVE: Few studies to date have explored the question of the safety of a hospital stay from the patient's point of view. The aim of this study was to describe patients' own perspectives on the safety of the surgical care they received. A qualitative study was conducted based on interviews. METHODS: Semidirected interviews were conducted by a sociologist with adult patients admitted for hospitalization in 2 orthopedic and in 2 digestive surgery wards in 4 hospitals. RESULTS: Eighty interviews were transcribed and analyzed. The patients surveyed averaged 61.7 years old (SD, 16.0 y). Forty-eight percent were men (n = 38). The issue of the safety of care, as defined by professionals, is little apprehended by patients. In their view, sense of safety was related to the trust in the surgeon, which is a requisite condition for a sense of security and is based on interactions with the surgeon and on their communication style. Sense of safety was also related to the preoperative consultation, in which the procedure is explained and illustrated and to a postoperative encounter with a person who participated in the operation. CONCLUSIONS: Patients' sense of safety is linked to the amount of trust they have in their surgeons. New strategies to improve language practices and surgeon-patient interaction should be developed, along with organizational improvement guaranteeing that participants of the surgery debrief with the patient.The study has been registered at ClinicalTrials.gov (identifier: NCT02820545).

Strategies used by emergency care professionals to handle interpersonal difficulties with patients: a qualitative study.

OBJECTIVES: Identify the strategies implemented by emergency care professionals when facing tension and interpersonal violence from patients and their friends and family. DESIGN: Descriptive qualitative study based on 38 semidirective interviews. PARTICIPANTS: Doctors, nurses, nursing assistants and administrative staff. SETTING: Four emergency departments (EDs) from three French university hospitals. RESULTS: According to the medical professionals interviewed, the difficulties that they encounter with patients or their accompanying family members can be explained by a lack of understanding of the functioning of EDs, by a general increase in individualistic behaviours leading to a lack of civility or by deviant behaviours (related to toxic substance abuse or mental illness). While managing deviant behaviours may sometimes require a collective intervention, ED staff also implement what are essentially individual communication strategies (with the use of rational explanation, seduction and empathy), confrontation or flight to deal with interpersonal difficulties. CONCLUSIONS: Strategies used by staff members tend to be individualised for the most part, and some, such as confrontational or escape strategies, may not be adapted to all situations. In the face of difficulties between staff and patients, mediators, specialised in resolving conflict, could entrust some cases to professionals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT03139110).

Identification and characterization of human Mex-3 proteins, a novel family of evolutionarily conserved RNA-binding proteins differentially localized to processing bodies.

In Caenorhabditis elegans, the Mex-3 protein is a translational regulator that specifies the posterior blastomere identity in the early embryo and contributes to the maintenance of the germline totipotency. We have now identified a family of four homologous human Mex-3 genes, called hMex-3A to -3D that encode proteins containing two heterogeneous nuclear ribonucleoprotein K homology (KH) domains and one carboxy-terminal RING finger module. The hMex-3 are phosphoproteins that bind RNA through their KH domains and shuttle between the nucleus and the cytoplasm via the CRM1-dependent export pathway. Our analysis further revealed that hMex-3A and hMex-3B, but not hMex-3C, colocalize with both the hDcp1a decapping factor and Argonaute (Ago) proteins in processing bodies (P bodies), recently characterized as centers of mRNA turnover. Taken together, these findings indicate that hMex-3 proteins constitute a novel family of evolutionarily conserved RNA-binding proteins, differentially recruited to P bodies and potentially involved in post-transcriptional regulatory mechanisms.

Integrative analysis of RUNX1 downstream pathways and target genes.

BACKGROUND: The RUNX1 transcription factor gene is frequently mutated in sporadic myeloid and lymphoid leukemia through translocation, point mutation or amplification. It is also responsible for a familial platelet disorder with predisposition to acute myeloid leukemia (FPD-AML). The disruption of the largely unknown biological pathways controlled by RUNX1 is likely to be responsible for the development of leukemia. We have used multiple microarray platforms and bioinformatic techniques to help identify these biological pathways to aid in the understanding of why RUNX1 mutations lead to leukemia. RESULTS: Here we report genes regulated either directly or indirectly by RUNX1 based on the study of gene expression profiles generated from 3 different human and mouse platforms. The platforms used were global gene expression profiling of: 1) cell lines with RUNX1 mutations from FPD-AML patients, 2) over-expression of RUNX1 and CBFbeta, and 3) Runx1 knockout mouse embryos using either cDNA or Affymetrix microarrays. We observe that our datasets (lists of differentially expressed genes) significantly correlate with published microarray data from sporadic AML patients with mutations in either RUNX1 or its cofactor, CBFbeta. A number of biological processes were identified among the differentially expressed genes and functional assays suggest that heterozygous RUNX1 point mutations in patients with FPD-AML impair cell proliferation, microtubule dynamics and possibly genetic stability. In addition, analysis of the regulatory regions of the differentially expressed genes has for the first time systematically identified numerous potential novel RUNX1 target genes. CONCLUSION: This work is the first large-scale study attempting to identify the genetic networks regulated by RUNX1, a master regulator in the development of the hematopoietic system and leukemia. The biological pathways and target genes controlled by RUNX1 will have considerable importance in disease progression in both familial and sporadic leukemia as well as therapeutic implications.

Evaluation of an interactive program for preventing adverse drug events in primary care: study protocol of the InPAct cluster randomised stepped wedge trial.

BACKGROUND: Adverse drug events could often be prevented. One of their main causes is that patients rarely know how to detect them. Another cause is inadequate communication between patients and physicians. If patients were to be effectively trained in detecting and reporting adverse drug events, this should help to prevent their occurrence and subsequent complications. Our purpose is to present the protocol of the InPAct trial, which aims to evaluate an interactive program that encourages patients to report adverse drug events in primary care. METHODS/DESIGN: We will conduct a cluster randomised controlled stepped wedge trial, with eight clusters of 10 general practitioners each. The physicians will suggest to all of their antihypertensive-treated patients that they take part in this study. The InPAct program will be implemented in the clusters in random order along five successive three-month periods. Two new clusters will be trained in implementing the program at each step. The program features: an interactive patient booklet including informative paragraphs, several care plans and adverse drug event report forms; and standardised training of physicians in how to present the booklet to the patient. The primary outcome will be the reporting of adverse drug events by patients to their physician within three months. We assume that the number of patients reporting at least one adverse drug event will increase from 3% before program implementation to 7.5% afterward (coefficient of variation = 0.5, α = 0.05, ß = 0.2), which means that 1,200 patients must be included. The effect of the intervention on the main outcome will be quantified and tested using a mixed logistic model to integrate cluster and time effects. DISCUSSION: Our choice of a stepped wedge design is particularly appropriate for evaluating the implementation of a patient safety program within the constraints of general practice. We describe the InPAct intervention, which is an original program that is intended to improve communication between patients and physicians. Indeed, none of the previously published intervention studies has combined a patient education program and a patient reporting system for adverse drug events with the aim of improving patient safety in primary care. TRIAL REGISTRATION: This study is registered in ClinicalTrials.gov NCT01610817.

Interaction with 14-3-3 adaptors regulates the sorting of hMex-3B RNA-binding protein to distinct classes of RNA granules.

Stress granules (SG) and processing bodies (PBs) are cytoplasmic ribonucleoprotein particles whose assembly is induced by different stimuli. SG are the site of storage of untranslated transcripts formed in response to environmental stress, whereas PBs are involved in mRNA turnover. We recently characterized a novel family of four human proteins related to the Caenorhabditis elegans Mex-3, a RNA binding protein involved in the establishment of the anterior-posterior embryonic asymmetry and in the maintenance of germline pluripotency. We now report that the adaptor proteins 14-3-3 bind to hMex-3B but not to the three other hMex-3 family members. Serine 462, when phosphorylated, is the major 14-3-3 docking site on hMex-3B, and manipulation of this interaction reveals that 14-3-3 both stabilizes hMex-3B and modulates its ability to bind RNA. Furthermore, the complex formed between hMex-3B and Argonaute proteins is excluded from PBs when the interaction with 14-3-3 is disrupted, whereas the recruitment to SG is not affected. Thus, 14-3-3 exerts combined effects on hMex-3B and acts as a major regulator of the sorting between distinct classes of RNA granules.

LKB1 interacts with and phosphorylates PTEN: a functional link between two proteins involved in cancer predisposing syndromes.

Germline mutations of the LKB1 (STK11) tumor suppressor gene lead to Peutz-Jeghers syndrome (PJS) and predisposition to cancer. LKB1 encodes a serine/threonine kinase generally inactivated in PJS patients. We identified the dual phosphatase and tumor suppressor protein PTEN as an LKB1-interacting protein. Several LKB1 point mutations associated with PJS disrupt the interaction with PTEN suggesting that the loss of this interaction might contribute to PJS. Although PTEN and LKB1 are predominantly cytoplasmic and nuclear, respectively, their interaction leads to a cytoplasmic relocalization of LKB1. In addition, we show that PTEN is a substrate of the kinase LKB1 in vitro. As PTEN is a dual phosphatase mutated in autosomal inherited disorders with phenotypes similar to those of PJS (Bannayan-Riley-Ruvalcaba syndrome and Cowden disease), our study suggests a functional link between the proteins involved in different hamartomatous polyposis syndromes and emphasizes the central role played by LKB1 as a tumor suppressor in the small intestine.