Repurposing chlorpromazine to treat COVID-19: The reCoVery study.

OBJECTIVES: The ongoing COVID-19 pandemic has caused approximately 2,350,000 infections worldwide and killed more than 160,000 individuals. In Sainte-Anne Hospital (GHU PARIS Psychiatrie & Neuroscience, Paris, France) we have observed a lower incidence of symptomatic forms of COVID-19 among patients than among our clinical staff. This observation led us to hypothesize that psychotropic drugs could have a prophylactic action against SARS-CoV-2 and protect patients from the symptomatic and virulent forms of this infection, since several of these psychotropic drugs have documented antiviral properties. Chlorpromazine (CPZ), a phenothiazine derivative, is also known for its antiviral activity via the inhibition of clathrin-mediated endocytosis. Recentin vitro studies have reported that CPZ exhibits anti-MERS-CoV and anti-SARS-CoV-1 activity. METHODS: In this context, the ReCoVery study aims to repurpose CPZ, a molecule with an excellent tolerance profile and a very high biodistribution in the saliva, lungs and brain. We hypothesize that CPZ could reduce the unfavorable course of COVID-19 infection among patients requiring respiratory support without the need for ICU care, and that it could also reduce the contagiousness of SARS-CoV-2. For this purpose, we plan a pilot, multicenter, randomized, single blind, controlled, phase III therapeutic trial (standard treatment vs. CPZ+standard treatment). CONCLUSION: This repurposing of CPZ for its anti-SARS-CoV-2 activity could offer an alternative, rapid strategy to alleviate infection severity. This repurposing strategy also avoids numerous developmental and experimental steps, and could save precious time to rapidly establish an anti-COVID-19 therapy with well-known, limited and easily managed side effects.

[Repurposing of chlorpromazine in COVID-19 treatment: the reCoVery study]. / Repositionnement de la chlorpromazine dans le traitement du COVID-19 : étude reCoVery.

OBJECTIVES: The ongoing COVID-19 pandemic comprises a total of more than 2,350,000 cases and 160,000 deaths. The interest in anti-coronavirus drug development has been limited so far and effective methods to prevent or treat coronavirus infections in humans are still lacking. Urgent action is needed to fight this fatal coronavirus infection by reducing the number of infected people along with the infection contagiousness and severity. Since the beginning of the COVID-19 outbreak several weeks ago, we observe in GHU PARIS Psychiatrie & Neurosciences (Sainte-Anne hospital, Paris, France) a lower prevalence of symptomatic and severe forms of COVID-19 infections in psychiatric patients (∼4%) compared to health care professionals (∼14%). Similar observations have been noted in other psychiatric units in France and abroad. Our hypothesis is that psychiatric patients could be protected from severe forms of COVID-19 by their psychotropic treatments. Chlorpromazine (CPZ) is a phenothiazine derivative widely used in clinical routine in the treatment of acute and chronic psychoses. This first antipsychotic medication has been discovered in 1952 by Jean Delay and Pierre Deniker at Sainte-Anne hospital. In addition, to its antipsychotic effects, several in vitro studies have also demonstrated a CPZ antiviral activity via the inhibition of clathrin-mediated endocytosis. Recently, independent studies revealed that CPZ is an anti-MERS-CoV and an anti-SARS-CoV-1 drug. In comparison to other antiviral drugs, the main advantages of CPZ lie in its biodistribution: (i) preclinical and clinical studies have reported a high CPZ concentration in the lungs (20-200 times higher than in plasma), which is critical because of the respiratory tropism of SARS-CoV-2; (ii) CPZ is highly concentrated in saliva (30-100 times higher than in plasma) and could therefore reduce the contagiousness of COVID-19; (iii) CPZ can cross the blood-brain barrier and could therefore prevent the neurological forms of COVID-19. METHODS: Our hypothesis is that CPZ could decrease the unfavorable evolution of COVID-19 infection in oxygen-requiring patients without the need for intensive care, but also reduce the contagiousness of SARS-CoV-2. At this end, we designed a pilot, phase III, multicenter, single blind, randomized controlled clinical trial. Efficacy of CPZ will be assessed according to clinical, biological and radiological criteria. The main objective is to demonstrate a shorter time to response (TTR) to treatment in the CPZ+standard-of-care (CPZ+SOC) group, compared to the SOC group. Response to treatment is defined by a reduction of at least one level of severity on the WHO-Ordinal Scale for Clinical Improvement (WHO-OSCI). The secondary objectives are to demonstrate in the CPZ+SOC group, compared to the SOC group: (A) superior clinical improvement; (B) a greater decrease in the biological markers of viral attack by SARS-CoV-2 (PCR, viral load); (C) a greater decrease in inflammatory markers (e.g. CRP and lymphopenia); (D) a greater decrease in parenchymal involvement (chest CT) on the seventh day post-randomization; (E) to define the optimal dosage of CPZ and its tolerance; (F) to evaluate the biological parameters of response to treatment, in particular the involvement of inflammatory cytokines. Patient recruitment along with the main and secondary objectives are in line with WHO 2020 COVID-19 guidelines. CONCLUSION: This repositioning of CPZ as an anti-SARS-CoV-2 drug offers an alternative and rapid strategy to alleviate the virus propagation and the infection severity and lethality. This CPZ repositioning strategy also avoids numerous developmental and experimental steps and can save precious time to rapidly establish an anti-COVID-19 therapy with well-known, limited and easy to manage side effects. Indeed, CPZ is an FDA-approved drug with an excellent tolerance profile, prescribed for around 70 years in psychiatry but also in clinical routine in nausea and vomiting of pregnancy, in advanced cancer and also to treat headaches in various neurological conditions. The broad spectrum of CPZ treatment - including antipsychotic, anxiolytic, antiemetic, antiviral, immunomodulatory effects along with inhibition of clathrin-mediated endocytosis and modulation of blood-brain barrier - is in line with the historical French commercial name for CPZ, i.e. LARGACTIL, chosen as a reference to its "LARGe ACTion" properties. The discovery of those CPZ properties, as for many other molecules in psychiatry, is both the result of serendipity and careful clinical observations. Using this approach, the field of mental illness could provide innovative therapeutic approaches to fight SARS-CoV-2.

[The next psychoactive drugs: From imipramine to ketamine]. / Psychotropes du futur : de l'imipramine à la kétamine.

Since the 1950s, the therapeutic arsenal against depression has grown considerably. From the discovery of monoamine oxidase inhibitors (MAOI) to the antidepressant effect of ketamine, these pharmacological breakthroughs made the history of psychiatry. They also guided the research about the pathophysiology of depression, one of the most devasting diseases, which affects between 10 and 20 % of general population. In this article, we offer a short historical review of the various therapeutic options developed over the past century and the consequences of these innovations. We then review the most recent one, ketamine (and its enantiomer S, esketamine). Ketamine's effects are spectacular both in terms of their very short onset time, and because they are observed even in treatment-resistant depression. Just as MAOIs and tricyclic antidepressants allowed the "monoaminergic hypothesis of depression" to emerge, to unravel the mechanisms of ketamine's antidepressant effects should allow the understanding of the role of glutamatergic system, or that of neuro-inflammation, in the neurobiology of depression. Ketamine might also help to refine our understanding of the cognitive pathophysiology of depression, or even to deeply transform the clinical representations about what depression is.

Confidence and psychosis: a neuro-computational account of contingency learning disruption by NMDA blockade.

A state of pathological uncertainty about environmental regularities might represent a key step in the pathway to psychotic illness. Early psychosis can be investigated in healthy volunteers under ketamine, an NMDA receptor antagonist. Here, we explored the effects of ketamine on contingency learning using a placebo-controlled, double-blind, crossover design. During functional magnetic resonance imaging, participants performed an instrumental learning task, in which cue-outcome contingencies were probabilistic and reversed between blocks. Bayesian model comparison indicated that in such an unstable environment, reinforcement learning parameters are downregulated depending on confidence level, an adaptive mechanism that was specifically disrupted by ketamine administration. Drug effects were underpinned by altered neural activity in a fronto-parietal network, which reflected the confidence-based shift to exploitation of learned contingencies. Our findings suggest that an early characteristic of psychosis lies in a persistent doubt that undermines the stabilization of behavioral policy resulting in a failure to exploit regularities in the environment.

Distinct alterations in probabilistic reversal learning across at-risk mental state, first episode psychosis and persistent schizophrenia.

We used a probabilistic reversal learning task to examine prediction error-driven belief updating in three clinical groups with psychosis or psychosis-like symptoms. Study 1 compared people with at-risk mental state and first episode psychosis (FEP) to matched controls. Study 2 compared people diagnosed with treatment-resistant schizophrenia (TRS) to matched controls. The design replicated our previous work showing ketamine-related perturbations in how meta-level confidence maintained behavioural policy. We applied the same computational modelling analysis here, in order to compare the pharmacological model to three groups at different stages of psychosis. Accuracy was reduced in FEP, reflecting increased tendencies to shift strategy following probabilistic errors. The TRS group also showed a greater tendency to shift choice strategies though accuracy levels were not significantly reduced. Applying the previously-used computational modelling approach, we observed that only the TRS group showed altered confidence-based modulation of responding, previously observed under ketamine administration. Overall, our behavioural findings demonstrated resemblance between clinical groups (FEP and TRS) and ketamine in terms of a reduction in stabilisation of responding in a noisy environment. The computational analysis suggested that TRS, but not FEP, replicates ketamine effects but we consider the computational findings preliminary given limitations in performance of the model.

Caries experience and related factors in 4-6 year-olds attending dental clinics in Kinshasa, DR of Congo.

OBJECTIVES: The aim of this study was to examine the prevalence and severity of caries experience (CE) in 4-6 year-olds attending dental clinics in Kinshasa, DR Congo, and to explore possible associations with reported behavioural and socio-demographic factors. METHODS: A convenience sample of children attending five dental clinics was recruited. Carers, usually parents, completed a questionnaire consisting of socio-demographic information, oral health and tobacco consumption profile of parents, socio-economic family situation and oral health habits of the child. Children were clinically examined using WHO criteria by trained dentist-examiners. To investigate factors associated with CE, multivariate logistic regression was applied with the significance level set at 0.05. RESULTS: Some 158 children with mean age 5.3 (sd 0.7) years were recruited; 80% presented with clinical signs of CE. Between-meal snacking and drinking was reported by 78% and 65%; 35% had sugar-containing drinks. Most (81%) brushed once a day and 82% brushed in the morning. Prevalence of CE was associated with gender, frequency of meals, consumption of drinks during meals and consumption of sugar-containing drinks; severity with type of infant feeding and sugar-content of the last meal at night. CONCLUSION: The present study shows that both prevalence and severity of caries experience were associated with reported dietary habits, confirming the importance of preventive interventions dealing with these habits in young children living in a developing country.

Jean Talairach (1911-2007). An untold story of the pioneer of stereotactic and functional neurosurgery.

CONTEXT: The Department of neurosurgery of the Sainte-Anne Hospital hosted Jean Talairach who created and developed stereotactic neurosurgery in France. Despite numerous neurosurgical and neuroscientific achievements, little is known about the life of Jean Talairach. METHODS: Systematic screening of Sainte-Anne Hospital Museum, Henry Ey Library, and Bibliothèque Inter-Universitaire de Santé funds, and medical databases using the term "Jean Talairach". RESULTS: Jean Talairach started his medical career at the Sainte-Anne Hospital in 1942 as a psychiatrist and became a neurosurgeon due to his interest in stereotactic neurosurgery. During World War II, Jean Talairach joined the French Resistance in Paris, then the French First Army. Jean Talairach created an original and specific stereotactic methodology with appropriate stereotactic frame and tools and performed one of the first human stereotactic surgeries in 1948. He described the reference lines passing by the anterior and posterior commissures in 1952 and developed a tridimensional co-planar stereotactic atlas of the human brain. With the collaboration of Jean Bancaud, he created stereo-electroencephalography to investigate patients suffering from drug-resistant epilepsy. The "Sainte-Anne school" trained French and foreign stereotactic and functional neurosurgeons ensuring the spread of Jean Talairach's innovative ideas. Jean Talairach retired in 1980. CONCLUSION: Jean Talairach's achievements encapsulate the evolution of neurosurgery in France during the 20th century. He developed an original stereotactic methodology including a tridimensional stereotactic atlas of the human brain and a stereotactic frame. He created stereo-electroencephalography, which remains the gold-standard to investigate patients suffering from drug-resistant epilepsy.

Accuracy and surgical feasibility of a CBCT-based stereolithographic surgical guide aiding autotransplantation of teeth: in vitro validation.

The aims of this study were to determine the accuracy of a 3D computer model and stereolithographic (STL) replica when compared to the real tooth and to develop a cone beam computed tomography (CBCT)-based planning technique including surgical guide fabrication. A STL surgical guide and a tooth replica were fabricated using SimPlant Pro 12.1. To validate this process, tooth segmentation and replica design were prepared for comparison to an optical scan of the corresponding tooth. For surgical intervention, a dry dentate mandible was scanned using a Scanora CBCT and the donor tooth was segmented. The donor tooth was repositioned, and two guides were designed. These tooth replica and guides were used in socket preparation of the dry mandible. The 3D computer model of the segmented teeth and related STL models showed satisfactory results with an acceptable accuracy. The surfaces were within 0·25mm distance, but in some areas up to 2·5mm deviation were seen. The results showed that 79% of the points was between 0·25 and -0·25mm, 3% was overestimated (>0·25mm) and 18% was underestimated (<-0·25mm). The computer-based repositioning of the donor tooth and construction of tooth replica and guide allowed socket preparation before donor tooth extraction and optimization of the STL procedure for in vivo planning of CBCT-based autotransplantation.

Subdural hematoma and electroconvulsive therapy: A case report and review of the literature.

BACKGROUND AND CASE PRESENTATION: Electroconvulsive therapy (ECT) is a common therapeutic procedure in psychiatry associated with a low rate of complications. We report a rare case of subdural hematoma (SDH) associated with ECT. CLINICAL PRESENTATION: a 64 year old woman, with a medical history of persistent depression which required ECT six years previously, underwent ECT following a new acute episode. After four ECT sessions, a left hemiparesis occurred. Brain CT scan revealed a right SDH. The patient underwent surgery and fully recovered three months after the drainage of the hematoma. We conducted a review of all cases in which SDH was associated to ECT. CONCLUSION: Early stage brain imaging is indispensable prior to starting ECT. Moreover, a previous medical history of SDH may not be a contraindication to ECT. In these situations, a clinical and radiological follow-up by both the psychiatrist and the neurosurgeon during all the ECT sessions is highly recommended.

Anhedonia predicts poor psychosocial functioning: Results from a large cohort of patients treated for major depressive disorder by general practitioners.

BACKGROUND: Anhedonia is a core symptom of major depression and a key prognostic factor that is often poorly explored in clinical trials of major depressive disorder (MDD). Beyond symptomatic remission, psychosocial functioning also reveals difficulty in achieving remission in patients with MDD. The main objective of this study was to explore the interrelationships between social functioning and anhedonia on a longitudinal basis. METHODS: In total, 1570 outpatients treated for MDD with agomelatine were included. Severity of depression and levels of anhedonia and of psychosocial functioning were assessed at inclusion and at 10-14 weeks, with specific standardized scales (MADRS, QFS, SHAPS, CGI). Multivariate regression and mediation analyses were performed. RESULTS: Using multivariate regression, we showed that improvement of anhedonia was the strongest predictor of improvement in psychosocial functioning (odds ratio=7.3 [4.3-12.1] P<0.0001). In addition, mediation tests confirmed that the association between improvement of depressive symptoms and improvement of social functioning was significantly underpinned by the improvement of anhedonia over time. Finally, we explored the determinants of the dissociation of the response, i.e., the persistence of psychosocial dysfunctioning despite a symptomatic response to antidepressant treatment, which remains a widespread situation in clinical practice. We showed that this dissociation was strongly predicted by persistence of anhedonia. CONCLUSION: Our results suggest that anhedonia is one of the strongest predictors of psychosocial functioning, along with symptomatic remission, and should be carefully assessed by health professionals, in order to optimize pharmacological as well as non-pharmacological management of depression.

Tooth transplantations: a descriptive retrospective study.

The aim of the present study was to perform a retrospective study of autogeneously transplanted teeth in order to examine the influence of clinical criteria such as the type of the donor tooth, the root length at the time of transplantation, donor eruption stage and others on the overall success rate of the transplantation. The material of this study consisted of 194 patients in whom 273 teeth were transplanted. The mean age at the time of autotransplantation was 18.1 years with a standard deviation of 7.5 years. Transplantations were performed in two hospitals. The follow-up period varied from 15 days to 11 years, and the mean follow-up time was 3.8 years. 58/273 teeth showed one or other form of resorption, 37/273 teeth showed ankylosis, 30/273 showed no important changes in pulp chamber size, 104/273 showed major discoloration after transplantation, 92/273 teeth showed positive results for cold test after transplantation and 26/273 teeth showed clinically unacceptable pocket depth. Clinical and radiological evaluations were performed. An association was found between successful transplantation and donor tooth type (P<0.01), root length at the time of transplantation (P<0.0001) and recipient tooth site (P=0.03). There was a borderline association between successful transplantation and donor eruption stage (P=0.05). In conclusion, autotransplantation of teeth performed with a careful surgical procedure at the stage of 1/2-3/4 of their intended or expected root length can render a very useful service to patients.

[The combination of a fused tooth and a supernumerary central incisor: a possible treatment plan]. / Het samen voorkomen van een dubbeltand en een boventallig gebitselement. Een mogelijke behandeling.

An 8-year old boy was referred to the orthodontic department because of a fused tooth. The clinical and radiological examination showed that - besides the double tooth at the region of the 21 - there was a normal tooth 22 in eruption as well. Moreover a still impacted supernumerary tooth was present in the right upper front region. The treatment included the extraction of the fused tooth and an autotransplantation of the supernumerary tooth to the extraction site of the fused tooth. During the follow-up period the pulp showed a progressive obliteration starting at the crown level with a conservation of the vitality. Apexification of the root of the transplanted tooth proceeded successfully. Furthermore a review of the literature is given in this article on the aetiology and treatment of fused teeth and on the application of autotransplantation.

Quantitative determination of immunological components of salivary gland secretion in transplant recipients.

Cancer therapies often induce oral complications. We studied longitudinally the major salivary immunoglobulin content in 42 transplant recipients using an enzyme-linked immunosorbent assay. A dramatic decrease in both sIgA and IgG is noticed post-transplant compared to pretransplant values. Only a small recovery of these immunoglobulin concentrations is seen after approximately 4 months. The reduction of sIgA and IgG in saliva could contribute to the frequent oral complications seen in these patients after transplantation and increase the risk of developing dental caries.

Wound healing following dental extractions in rabbits: effects of tranexamic acid, warfarin anti-coagulation, and socket packing.

We have investigated the importance of the coagulation and fibrinolytic systems for wound healing following dental extractions. Four front teeth were extracted in rabbits; wound healing was measured as time until complete epithelial closure. The antifibrinolytic agent tranexamic acid shortened duration of wound healing in normal rabbits. Anti-coagulation with warfarin delayed epithelial closure, which was, however, normalized by simultaneous administration of tranexamic acid, whereas complete packing of the socket with oxidized cellulose had no corrective effect. Apical packing together with tranexamic acid gave normal healing. It is concluded that the quality of the fibrin network within the dental socket determines the rate of wound healing; oxidized cellulose is not an adequate substitute for fibrin.

Influence of anticoagulation on blood loss following dental extractions.

The coagulation activity level at which oral surgery procedures can be performed in anticoagulated patients without triggering bleeding complications and without enhancing the risk of developing thrombo-embolic events remains controversial. The objective of the present study was to evaluate blood loss following dental extractions at different levels of anticoagulation and to determine its effect on wound closure rates. Blood loss was measured following the removal of four front teeth in warfarinized rabbits. Immediate blood loss was evaluated by determining the tooth socket bleeding times and by using a technique based on hemoglobin determinations. Long-term blood loss was assessed by comparison of labeled red-blood-cell disappearance curves. The results showed that blood loss following dental extractions was significantly greater in animals anticoagulated at a therapeutic level than in non-anticoagulated control animals. Determination of blood loss at different levels of anticoagulation clearly demonstrated that complete correction of the coagulation activity was unnecessary. Partial correction (INR values of 1.6-1.8) allowed extractions to be performed without extensive blood loss. With this technique of partial correction, the period of interruption of the anticoagulation could be kept very short, and the risk of postoperative bleeding complications was minimal. Wound closure rates were negatively influenced in anticoagulated animals.

Oral hygiene in 12-year-old disabled children in Flanders, Belgium, related to manual dexterity.

As part of a larger epidemiological survey of a stratified sample of 12-year-old handicapped children in Flanders, Belgium, the present study describes gingival health, gingival hypertrophy, oral cleanliness and the presence of calculus. Statistical analysis was performed with motor skills, brushing help, the use of chemical agents, the use of anti-epileptic drugs, the knowledge of parents and educators (or caregivers) and their opinion of the oral hygiene of their children/ pupils as response variables. From this study, it became clear that mildly mentally retarded and learning-impaired children had significantly better manual dexterity skills than moderately and severely mentally retarded and physically impaired children. However, this was not reflected in improved oral hygiene. The use of chemical plaque controlling agents was found to be extremely low and, with the exception of children with gingival hyperplasia, the users of these agents did not have better oral hygiene. No difference was found between subtypes in the opinion of parents and educators on oral status. There was, however, a difference between their assessment and the clinical picture. It was concluded that there was a need for in-service training programmes in oral health care for educators as well as for parents.

Oral health condition of 12-year-old handicapped children in Flanders (Belgium).

The dental condition of 626 12-year-old handicapped children with mild mental or moderate to severe mental retardation or learning impairment, being 25% of the population of each of these groups, was examined in Flanders. An evaluation of oral cleanliness showed poor oral hygiene in 31.8% of the children. No significant differences were found in oral cleanliness among types of handicapping conditions. The mean DMFT score was 2.9 (s: 2.6) and DMFS score was 5.4 (s: 5.6). Almost 21% of the children were free of caries or fillings. No significant differences were found among groups of handicapped children. Handicapped children presented a low level of restorative care (restorative index score: 48.7%). Mildly mentally retarded children demonstrated the lowest restorative index (43.9%). The caries experience of first permanent molars represented the largest part of the DMFT score (64.1%). Sealants were present in 7.9% of children examined. A considerable percentage of mildly mentally retarded children and learning impaired children did not brush daily (22.1% and 20.9%) and did not receive help with toothbrushing from their parents or carers (91.0% and 94.7%, respectively).

Quantitative determination of immunologic components of salivary gland secretion in long-term, event-free pediatric oncology patients.

OBJECTIVES: Chemotherapy influences the human immune system. Salivary alterations occur during cancer treatment. In this article we examine the salivary immunoglobulin content in pediatric patients who were long-term event-free and correlate these findings with different oral factors. STUDY DESIGN: Fifty-two children of a study group and 63 children of a control group were examined at our University Hospital. Caries prevalence and plaque index were scored. Whole saliva samples were taken for determination of slgA and IgG concentrations and Streptococcus mutans and Lactobacillus counts. For statistical analysis the Dental Survey Plus (Providence Software Services, Bristol, England) software package was used. RESULTS: Concentrations of slgA and IgG were within normal limits in both groups; slgA level increased with age. A negative correlation between slgA concentration and caries experience was not found in all age groups. No correlation with other salivary parameters was found. CONCLUSION: Salivary content of slgA and IgG can return to normal after cytotoxic therapy in these children. Salivary IgA seem to play a role in the development of dental caries in this population.

Caries-related salivary microorganisms and salivary flow rate in bone marrow recipients.

Cancer treatments often induce oral complications. In this study we investigate longitudinally the salivary gland function, the salivary caries-related microorganisms, and buffer capacity in bone marrow recipients. Stimulated saliva samples were taken midmorning. The salivary factors were studied in 42 patients from before transplant until 4 months after transplant. A dramatic reduction (66%) of salivary flow rate is noticed in all patients at 1 month after transplant, and only a partial recovery (42% reduction) is seen after 4 months. A clear shift toward a lower buffer capacity and a higher amount of cariogenic microorganisms is seen posttransplant. This shift is more pronounced when total body irradiation was included in the pretransplant conditioning therapy. These findings indicate that the studied parameters in transplant recipients can contribute to a higher caries risk and oral complications during the early posttransplant period.

The validity of a medical risk-related history for dental patients in Belgium.

The aim of this study was to establish whether a patient-administered medical risk-related history (MRRH) for dental patients was valid. The MRRH, which was developed in the Netherlands, has now been tested in Belgium, where it was completed by total of 99 patients. Their answers were compared with the results of a verbal history, taken by a physician experienced in pre-assessment control. This verbal history was considered the 'gold standard'. The sensitivity and specificity of the medical questionnaire proved to be sufficiently high (88 per cent and 98 per cent respectively) and Cohen's Kappa displayed close agreement (0.87). These figures were only slightly lower than those obtained in Holland. The MRRH is valid for the registration of medical problems in dental patients but the answers need to be checked personally by the dental practitioner. Since the present trial was a limited one, the study will be expanded to nine countries in Europe.