Validating a blood donation awareness tool created using general practitioner and patient acceptability and preferences.

BACKGROUND: There is a need to develop an awareness raising tool for GPs to reach out their patients in order to increase blood donation. The main objective was to create and validate a tool to raise awareness about blood donation that meets acceptability and preference criteria and is applicable in general practice. MATERIAL AND METHODS: This cross-sectional study was conducted in three phases. 1. Tool creation: A stakeholder meeting co-developed three potential tools to raise awareness about blood donation: a consulting room poster, a waiting room poster and a lapel badge for the doctor. Three GPs pilot-tested each tool for one day during their regular consultations. Then, once the pilot was completed each GP assessed acceptability and preference using a semi-structured interview, and patients were also interviewed. 2. Consensual tool selection: An appropriate tool was selected based on pilot data using nominal group technique and expert review. 3. The tool was validated for its acceptability in practice via a quantitative questionnaire distributed electronically to GPs. RESULTS: The consensual tool selected by the nominal group was a combination of elements from all three tools trialled in the pilot, reported to be non-intrusive and convenient for both GPs and patients. Patient responses indicated a high level of acceptability and indicated a strong preference for self-generated discussion of the topic with their GP. In the validation step, 217 responses to the quantitative questionnaire were received: 74.5% of responses fulfilled the acceptability criteria for using this combined tool in general practice. Furthermore, 93.1% of GPs indicated they would use the tool in the proposed format for the purpose of raising awareness. DISCUSSION: The validation of our blood donation awareness tool for use in general practice justifies its evaluation on a larger scale as part of a wider blood donation awareness campaign.

[Psychiatry without mind?] / Une psychiatrie sans esprit ?

Philosophy of Mind is currently one of the most prolific fields of research in philosophy and has witnessed a progressive hybridization with cognitive science. It focuses on fundamental questions to neuroscience and psychiatry, such as the nature of mental states and cognitive processes, or the relationships between mental states and the world. Anticipating the accumulation of experimental data from neuroscience, it provides a framework for the generation of theories in cognitive science. Philosophy of mind has thus laid the foundations of the conceptual space within which cognitive sciences have spread: a large part of contemporary theories in cognitive science result from a hybridization of conceptions forged by philosophers of mind and data produced by neuroscientists. Yet contemporary psychiatry is still reluctant to feed on the philosophy of mind, other than through the fragments that emerge from neuroscience. In this paper, we describe the evolution of contemporary philosophy of mind, and we detail its contributions around three central themes for psychiatry: naturalization of mind, mental causality, and subjectivity of mental states. We show how philosophy of mind provide the conceptual framework to link different levels of explanation in psychiatry: from biological to functional, from neurophysiology to cognition, from matter to mind.

Ensuring mental health care during the SARS-CoV-2 epidemic in France: A narrative review.

OBJECTIVE: The lack of resources and coordination to face the coronavirus epidemic raises concerns for the health of patients with mental disorders in a country where we still have memories of the dramatic experience of famine in psychiatric hospitals during the Second World War. This article aims to propose guidance to ensure mental health care during the SARS-CoV epidemic in France. METHODS: The authors performed a narrative review identifying relevant results in the scientific and medical literature and in local initiatives in France. RESULTS: We identified four types of major vulnerabilities among patients with mental disorders during this pandemic: (1) medical comorbidities that are more frequently found among patients with mental disorders (cardiovascular and pulmonary pathologies, diabetes, obesity, etc.) which are risk factors for severe covid-19 infection; (2) age (the elderly form the population most vulnerable to the coronavirus); (3) cognitive and behavioural disorders, which can hamper compliance with confinement and hygiene measures and finally and (4) psychosocial vulnerability as a result of stigmatization and/or socio-economic difficulties. Furthermore, the mental health healthcare system is more vulnerable than other healthcare systems. Current government plans are poorly suited to psychiatric establishments in a context of major shortages of organizational, material and human resources. In addition, a certain number of structural aspects make the psychiatric institution particularly vulnerable: many beds have been closed, wards have high densities of patients, mental health community facilities are closed, and medical teams are understaffed and poorly trained to face infectious diseases. There are also major issues when referring patients with acute mental disorders to intensive care units. To maintain the continuity of psychiatric care in this pandemic situation, several directions can be considered, in particular with the creation of "COVID+ units". These units are under the dual supervision of a psychiatrist and an internist/infectious disease specialist; all new entrants are placed in quarantine for 14 days; the nursing staff receives specific training, daily medical check-ups and close psychological support. Family visits are prohibited and replaced by videoconference. At the end of hospitalization, in particular for the population of patients in compulsory ambulatory care situations, specific case-management are organized with the possibility of home visits, in order to support patients when they get back home and to help them cope with the experience of confinement, which is liable to induce recurrences of mental disorders. The total or partial closure of community mental health facilities is particularly disturbing for patients, but a regular follow-up is possible with telemedicine and should include the monitoring of suicide risk and psycho-education strategies; developing support platforms could also be very helpful in this context. Private practice psychiatrists also have a crucial role of information towards their patients on confinement and barrier measures, and also on measures to prevent the psychological risks inherent in confinement: maintenance of regular sleep r, physical exercise, social interactions, stress management and coping strategies, prevention of addictions, etc. They should also be trained to prevent, detect and treat early warning symptoms of post-traumatic stress disorder, because their prevalence was high in the regions of China most affected by the pandemic. DISCUSSION: French mental healthcare is now facing a great and urgent need for reorganization and must also prepare in the coming days and weeks to face an epidemic of emotional disorders due to the confinement of the general population.

[Psychopathological consequences of confinement]. / Conséquences psychopathologiques du confinement.

The psychological effects of isolation have already been described in the literature (polar expeditions, submarines, prison). Nevertheless, the scale of confinement implemented during the COVID-19 pandemic is unprecedented. In addition to reviewing the published studies, we need to anticipate the psychological problems that could arise during or at a distance from confinement. We have gone beyond the COVID-19 literature in order to examine the implications of the known consequences of confinement, like boredom, social isolation, stress, or sleep deprivation. Anxiety, post-traumatic stress disorder, depression, suicidal or addictive behaviours, domestic violence are described effects of confinement, but the mechanisms of emergence of these disorders and their interrelationships remain to be studied. For example, what are the mechanisms of emergence of post-traumatic stress disorders in the context of confinement? We also remind the reader of points of vigilance to be kept in mind with regard to eating disorders and hallucinations. Hallucinations are curiously ignored in the literature on confinement, whereas a vast literature links social isolation and hallucinations. Due to the broad psychopathological consequences, we have to look for these various symptoms to manage them. We quickly summarize the diagnostic and therapeutic approaches already in place, such as telemedicine, which is undergoing rapid development during the COVID-19 crisis.

[Ensuring mental health care during the SARS-CoV-2 epidemic in France: A narrative review]. / Assurer les soins aux patients souffrant de troubles psychiques en France pendant l'épidémie à SARS-CoV-2.

OBJECTIVE: The lack of ressources and coordination to face the epidemic of coronavirus raises concerns for the health of patients with mental disorders in a country where we keep in memory the dramatic experience of famine in psychiatric hospitals during the Second World War. This article aims at proposing guidance to ensure mental health care during the SARS-CoV epidemy in France. METHODS: Authors performed a narrative review identifying relevant results in the scientific and medical literature and local initiatives in France. RESULTS: We identified four types of major vulnerabilities in patients suffering from mental disorders during this pandemic: (1) medical comorbidities that are more frequently found in patients suffering from mental disorders (cardiovascular and pulmonary pathologies, diabetes, obesity, etc.) which represent risk factors for severe infections with Covid-19; (2) age (the elderly constituting the population most vulnerable to coronavirus); (3) cognitive and behavioral troubles which can hamper compliance with confinement and hygiene measures and finally and (4) psychosocial vulnerability due to stigmatization and/or socio-economic difficulties. Furthermore, the mental health healthcare system is more vulnerable than other healthcare systems. Current government plans are poorly adapted to psychiatric establishments in a context of major shortage of organizational, material and human resources. In addition, a certain number of structural aspects make the psychiatric institution particularly vulnerable: many beds are closed, wards have a high density of patients, mental health community facilities are closed, medical teams are understaffed and poorly trained to face infectious diseases. We could also face major issues in referring patients with acute mental disorders to intensive care units. To maintain continuity of psychiatric care in this pandemic situation, several directions can be considered, in particular with the creation of Covid+ units. These units are under the dual supervision of a psychiatrist and of an internist/infectious disease specialist; all new entrants should be placed in quarantine for 14 days; the nurse staff should benefit from specific training, from daily medical check-ups and from close psychological support. Family visits would be prohibited and replaced by videoconference. At the end of hospitalization, in particular for the population of patients in compulsory ambulatory care situations, specific case-management should be organized with the possibility of home visits, in order to support them when they get back home and to help them to cope with the experience of confinement, which is at risk to induce recurrences of mental disorders. The total or partial closure of mental health community facilities is particularly disturbing for patients but a regular follow-up is possible with telemedicine and should include the monitoring of the suicide risk and psychoeducation strategies; developing support platforms could also be very helpful in this context. Private psychiatrists have also a crucial role of information with their patients on confinement and barrier measures, but also on measures to prevent the psychological risks inherent to confinement: maintenance of sleep regularity, physical exercise, social interactions, stress management and coping strategies, prevention of addictions, etc. They should also be trained to prevent, detect and treat early warning symptoms of post-traumatic stress disorder, because their prevalence was high in the regions of China most affected by the pandemic. DISCUSSION: French mental healthcare is now in a great and urgent need for reorganization and must also prepare in the coming days and weeks to face an epidemic of emotional disorders due to the containment of the general population.

The present and future of withdrawal period calculations for milk in the European Union: focus on heterogeneous, nonmonotonic data.

Harmonization of the method for calculating the withdrawal period for milk dates from the 1990s. European harmonization has led to guidance with three accepted methods for determining the withdrawal period for milk that are currently applicable. These three methods can be used by marketing authorization holders, but, in some cases, their diversity can lead to very different withdrawal periods. This is particularly the case when concentrations in milk are nonmonotonic and heterogeneous, meaning that concentrations strictly increase and then strictly decrease with significant interindividual variability in the time to reach the maximal concentration. Here, we first describe the concepts associated with the different methods used in the harmonized approach currently applicable for the determination of milk withdrawal periods, and then, we propose the application of a modern pharmacometric tool. Finally, with a nonmonotonic heterogeneous dataset, we illustrate the usefulness of this tool in comparison with the three currently applicable methods and discuss the limitations and advantages of each method.

The present and future of withdrawal period calculations for milk in the European Union: dealing with data below the limit of quantification.

The assessment of withdrawal periods for milk is affected by the occurrence of data below the lower analytical quantification limit (BLQ data) and the resulting uncertainty. The current regulatory approach for dealing with BLQ residues is simple and easy: BLQ data (and missing data) are arbitrarily reassigned a value of one-half the LOQ before any calculation on the data with one of the three currently applicable methods. Here, we reconsider the determination of the withdrawal period of milk with data below the limit of quantification. Theoretical background on analytical limits and pharmacometric considerations will be established. Then, we analyze the uncertainty problems caused by the current approach and propose a calculation solution (maximum-likelihood estimation handling left-censored data) included in nonlinear mixed-effects modeling. Finally, we illustrate this issue using a case example.

Hematopoietic stem cell transplantation in relapsed ALK+ anaplastic large cell lymphoma in children and adolescents: a study on behalf of the SFCE and SFGM-TC.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a treatment option for relapsed anaplastic large cell lymphoma (ALCL) in children, but reports on its efficacy in this disease are still limited. We analyzed data concerning 34 patients under 18 years of age prospectively registered in the French SFGM-TC database, who had undergone an allo-SCT for the treatment of ALK+ ALCL between 1993 and 2011. At transplant, 28 patients (82.4%) were in CR, whereas 6 exhibited detectable disease. Conditioning regimens were mostly myelo-ablative (n=31). With a median follow-up of 6 years, 5-year overall and event-free survival rates were 70% (SE=8%) and 58% (SE=9%), respectively. The 5-year cumulative incidence of relapse and treatment-related mortality was 18% (SE=7%) and 24% (SE=8%), respectively. Six patients had relapsed (median time, 141 days (35-235)). A durable CR had been obtained in 4/6 patients after injection of donor lymphocytes (n=1) or vinblastine-corticosteroid therapy (n=3). Ten patients had died, eight due to transplant toxicity and two due to progressive disease. Allo-SCT is an efficient treatment for pediatric patients with high-risk relapsed ALK+ ALCL. However, the overall morbidity of allo-SCT raises questions about its place, given the efficacy of targeted agents currently under development in this disease.

Random locomotion and chemotaxis of human blood polymorphonuclear leukocytes from a patient with leukocyte adhesion deficiency-1: normal displacement in close quarters via chimneying.

The beta2 integrins are known to be important in the motile function of leukocytes in general and in the adhesive response to inflammatory stimuli in particular. In the current study, under direct microscopic observation with concomitant time-lapse video recording, we examined the locomotion of human blood PMN from a patient with Leukocyte Adhesion Deficiency-1 (LAD), a disorder in which beta2 integrins on the cell surface are markedly deficient in number or function. In thin slide preparations such that the leukocytes were somewhat compressed between slide and cover slip, PMNLAD exhibited normal random locomotion and chemotaxis, apparently by using the opposing surfaces to generate the force for locomotion (chimneying). In thicker preparations, an adherence deficit was evident, but chemotaxis still occurred, even by PMNLAD anticoagulated in EDTA. Consistent with the paucity of beta2 integrins on the surface of the PMNLAD was their failure to aggregate in the presence of antibodies to beta2 integrins, even when they had been brought together by chemotaxis. We relate these findings to the reported independence from integrins of PMN in the lung vasculature in LAD, as well as in certain experimental conditions.

[Functions of neutrophil motility of human blood: locomotion and chemotaxis in simplified systems]. / Fonctions de motilité des polynucléaires du sang humain: locomotion et chimiotactisme dans des systèmes simplifiés.

Polymorphonuclear leukocytes (PMN, granulocytes) employ their plasma membranes and subjacent microfilament-rich peripheral cytoplasm for such motile functions as adherence and spreading, random locomotion, chemotaxis (directed locomotion), and phagocytosis. All of these functions are preserved in certain anucleate, granule-poor, cytoplasmic fragments (cytoplasts) derived from PMN. Thus, the sensing, transduncing, and effector capacities involved in these functions remain integrated without control from nuclei or from the other cellular organelles left behind when the cytoplast forms. More recently, we have begun to examine in intact PMN the role of divalent cations, which have been thought to be essential for motile function of leukocytes in general, and for the function of critical adhesion molecules in particular. In slide preparations under direct microscopic observation, EDTA (10 mM; to chelate divalent cations) did not impair either random locomotion or chemotaxis, nor did specific antibodies to beta-2 (CD 18) integrins or to other PMN integrins. Motile behavior appeared to benefit from the close approximation of slide and coverslip ("chimneying"). Thus, in "close quarters", PMN can generate the force for locomotion even when adhesion molecules are lacking or disabled. We relate these findings to the reported independence from integrins of PMN in certain experimental and diseases states.

Random locomotion and chemotaxis of human blood polymorphonuclear leukocytes (PMN) in the presence of EDTA: PMN in close quarters require neither leukocyte integrins nor external divalent cations.

Divalent cations are thought essential for motile function of leukocytes in general, and for the function of critical adhesion molecules in particular. In the current study, under direct microscopic observation with concomitant time-lapse video recording, we examined the effects of 10 mM EDTA on locomotion of human blood polymorphonuclear leukocytes (PMN). In very thin slide preparations, EDTA did not impair either random locomotion or chemotaxis; motile behavior appeared to benefit from the close approximation of slide and coverslip ("chimneying"). In preparations twice as thick, PMN in EDTA first exhibited active deformability with little or no displacement, then rounded up and became motionless. However, on creation of a chemotactic gradient, the same cells were able to orient and make their way to the target, often, however, losing momentarily their purchase on the substrate. In either of these preparations without EDTA, specific antibodies to beta2 integrins did not prevent random locomotion or chemotaxis, even when we added antibodies to beta1 and alphavbeta3 integrins and to integrin-associated protein, and none of these antibodies added anything to the effects of EDTA. In the more turbulent environment of even more media, effects of anti-beta2 integrins became evident: PMN still could locomote but adhered to substrate largely by their uropods and by uropod-associated filaments. We relate these findings to the reported independence from integrins of PMN in certain experimental and disease states. Moreover, we suggest that PMN locomotion in close quarters is not only integrin-independent, but independent of external divalent cations as well.

Chemotaxis by human neutrophils and their cytokineplasts treated with inhibitors of nitric oxide synthase: no suppression of orientation or trajectory.

Inhibitors of nitric oxide (NO) synthase are reported to inhibit both the adherence of polymorphonuclear leukocytes (PMN) to substrate and chemotaxis (directed locomotion) of PMN as determined in Boyden chamber assays. In the current study, we examined both human blood PMN and granule-poor motile cytoplasts derived from them (cytokineplasts, CKP), under direct microscopic observation with concomitant time-lapse video recording, for their ability to respond chemotactically to an erythrocyte destroyed by laser microirradiation. In this system we can observe directly and continuously the orientation and trajectory of PMN before, during, and after establishment of a chemotactic gradient. For both PMN and CKP we employed three different inhibitors of NO synthase (N(omega)-methyl-L-arginine, N-iminoethyl-L-ornithine, and diphenyleneiodonium) in at least twice the concentrations employed to inhibit chemotaxis of PMN in Boyden chambers or killing of bacteria in CKP. Although small differences in adhesion might not have been appreciated, treated PMN and CKP were each indistinguishable from untreated controls in their ability to orient in a newly created chemotactic gradient and in their trajectories toward the chemotactic target.

Visualization of intracellular calcium during necrotaxis.

Granulocytes are known to exhibit positive chemotaxis towards erythrocytes destroyed by laser irradiation (necrotaxis). A computerized method for visualizing intracellular calcium concentration in granulocytes during necrotaxis has been developed. Successive bursts of fluorescence were observed: 1 degree) about 10 s after the creation of the necrotactic source; 2 degrees) when the granulocyte touched the target.

Basket cells or shadow cells of Gumprecht: a scanning electron microscope study, and the correlation between percentages of basket cells, and cells with altered chromatin structure (dense cells), in chronic lymphocytic leukemia.

For over 50 years the received wisdom has been that the shadow cells of Gumprecht otherwise known as basket cells (BC) are in artefact, produced during preparation of films when a drop of blood is spread on a slide. The assumption has been that they are therefore of no significance. They are commonly seen in blood films from patients with lymphoproliferative syndromes and particularly in chronic lymphocytic leukemia (CLL). In 96 patients with CLL a statistically significant correlation existed between the basket cells observed in films and the lymphocytes with dense chromatin (DC) determined by flow-cytometry. There was no statistically significant correlation between the number of BC and DC, and the anatomic-clinical stage of the disease.

Cryopreserved cytoplasts from human polymorphonuclear leukocytes (cytokineplasts) are chemotactic at speeds comparable to those of fresh intact cells.

Cytokineplasts (CKP) are granule-poor cytoplasts from human polymorphonuclear leukocytes (PMN) that retain motile function, even (unlike the parent PMN) after cryopreservation. Employing time-lapse videomicroscopy, we examined the chemotactic properties of CKP after cryopreservation toward erythrocytes lysed by laser microirradiation. Paths of locomotion were plotted for six CKP in the field, and velocities were calculated at 10-sec intervals. Mean velocities of the six fragments, ranging from 9.3 to 20.8 microns/min, are of the order of fresh, intact PMN, the fastest of locomoting cells.

Locomotion of white blood cells: a biophysical analysis.

We determined some biophysical properties of human granulocytes, monocytes, and lymphocytes in respect to their locomotion. Granulocytes were exposed to plasma and were allowed to crawl on uncoated or glycol methacrylate coated glass plates. Monocytes did not migrate on uncoated glass, but did so on glycol methacrylated glass. Lymphocytes did not move on glass or glycol methacrylated glass, but moved on plexiglas coverslips. Granulocytes and monocytes showed a pronounced, directed movement towards a lysed erythrocyte (necrotaxis), lymphocytes showed no necrotactic response. The information collected by the granulocytes and monocytes in the necrotactic gradient was between 1 and 2 bits. This small amount of information indicated that the cellular decision in favor of a new direction of migration is based on a mechanism involving instability. We showed that the necrotactic response of granulocytes and monocytes is the product of the chemokinetic activity and the polar order parameter (= McCutcheon index) indicating that the cellular decision for a new direction of migration is independent of the speed of the cell movement. The movement of monocytes can be characterized in a similar way to that of granulocytes: the angle of deviation from a straight line path is nearly a fixed value (+/- 35 degrees). Lymphocytes stay in a restricted area after straight line movement. Particular attention was focused on cellular properties involved in locomotion. The characteristic time of the internal clock controlling the locomotion was 0.9 minutes for granulocytes and 2 minutes for monocytes. We were not able to determine the characteristic time of lymphocytes. We were able to determine the internal program responsible for the change in direction of movement. The directional memory time for granulocytes was 0.9 minutes. Monocytes had two directional memory times, short (2 minutes) and long (greater than 18 minutes). Lymphocytes had a very short directional memory time of 40 seconds. The distribution of the track velocities of migrating granulocytes and monocytes was described by bell shaped curves indicating homogeneous populations of cells. The distribution for lymphocytes had two maxima.

Galvanotaxis of human granulocytes. Dose-response curve.

The galvanotactic response of human granulocytes was investigated theoretically and experimentally. The basic results are: (i) The granulocytes move towards the anode. (ii) The directed movement has been quantified by two different polar order parameters--the McCutcheon index and the average of cos phi. (iii) The polar order parameters are a function of the applied electric field (= dose-response curve). (iv) The inverse of the galvanotactic constant of migrating cells (analogous to the Michaelis-Menten constant) has a value of -0.2 +/- 0.03 V/mm. (v) The galvanotactic response of granulocytes is a non-cooperative process with a cooperativity coefficient of 1 +/- 0.2. (vi) The galvanotactic constant is a function of pH. (vii) The protein essential for the galvanotactic response is very likely a G-protein.

Chemokinesis and necrotaxis of human granulocytes: the important cellular organelles.

The directed and non-directed locomotion of human polymorphonuclear leukocytes on a glass surface was compared to Brownian and drift motion. The average track velocity was measured under different conditions. The track velocity of colchicine treated cells was the same as control cells. However, cytochalasin B treated cells and cytokineplasts had a reduced track velocity compared with the control cells. The non-directed locomotion was investigated by measuring the mean square displacement as a function of time. The diffusion constant, D, which quantitates the random walk process, and the characteristic time, tau, which governs the migration of the cell, was calculated. The value of the diffusion constant depended on the cell treatment: For control cells 261 micron2/min, for colchicine treated cells 145 micron2/min, for cytochalasin B treated cells 55 micron2/min, and for cytokineplasts 47 micron2/min. The characteristic time was about 40 s. The measurement showed that the nondirected locomotion can be described by the Brownian motion. The directed locomotion was investigated by a necrotactic assay and quantitated by the McCutcheon index. This index was for control cells 0.85 +/- 0.07, for colchicine treated cells 0.8 +/- 0.07, and for cytokineplasts 0.75 +/- 0.1. The measurement showed that the directed locomotion can be described by a process which is called drift mode. From this method of analysis it was determined that the important organelles of the cell for the directed and the non-directed locomotion are: (i) A part of the plasma membrane, (ii) the microfilaments, and (iii) an unstructurated part of the cytoplasme. The microtubules of the cell are only of minor importance for the directed and the non-directed locomotion.