Directional control of neurite outgrowth: emerging technologies for Parkinson's disease using magnetic nanoparticles and magnetic field gradients.

A challenge in current stem cell therapies for Parkinson's disease (PD) is controlling neuronal outgrowth from the substantia nigra towards the targeted area where connectivity is required in the striatum. Here we present progress towards controlling directional neurite extensions through the application of iron-oxide magnetic nanoparticles (MNPs) labelled neuronal cells combined with a magnetic array generating large spatially variant field gradients (greater than 20 T m-1). We investigated the viability of this approach in both two-dimensional and organotypic brain slice models and validated the observed changes in neurite directionality using mathematical models. Results showed that MNP-labelled cells exhibited a shift in directional neurite outgrowth when cultured in a magnetic field gradient, which broadly agreed with mathematical modelling of the magnetic force gradients and predicted MNP force direction. We translated our approach to an ex vivo rat brain slice where we observed directional neurite outgrowth of transplanted MNP-labelled cells from the substantia nigra towards the striatum. The improved directionality highlights the viability of this approach as a remote-control methodology for the control and manipulation of cellular growth for regenerative medicine applications. This study presents a new tool to overcome challenges faced in the development of new therapies for PD.

The impact of the COVID-19 epidemic on primary care in South-eastern France: implementation of a real-time monitoring system based on regional health insurance system data.

BACKGROUND: The spring 2020 COVID-19 epidemic severely impacted France's healthcare system. The associated lockdown (17 March- 11 May 2020) and the risk of exposure to SARS-CoV-2 led patients to change their use of healthcare. This article presents the development and implementation of a real-time system to monitor i) private doctors' activity in South-eastern France, and ii) changes in prescription of drugs for people with diabetes, mental health disorders and for certain vaccines from Mars 2020 to October 2020. METHODS: Data extracted from the regional healthcare insurance databases for 2019 and 2020 were used to construct indicators of healthcare use. They were calculated on a weekly basis, starting from week 2 2020 and compared for the same period between 2019 and 2020. RESULTS: Private doctors' activity decreased during the spring 2020 lockdown (by 23 % for general practitioners and 46 % for specialists), followed by an almost complete return to normal after it ended until week 41. Over the same period, a huge increase in teleconsultations was observed, accounting for 30 % of private doctors' consultations at the height of the crisis. The start of the lockdown was marked by a peak in drug prescriptions, while vaccinations declined sharply (by 39 % for the measles, mumps and rubella (MMR) vaccine in children under 5 years old, and by 54 % for human papillomavirus vaccine in girls aged 10-14 years old). CONCLUSION: The ongoing COVID-19 epidemic may lead to health consequences other than those directly attributable to the disease itself. Specifically, lockdowns and foregoing healthcare could be very harmful at the individual and population levels. The latter issue is a concern for French public authorities, which have implemented actions aimed at encouraging patients to immediately seek treatment. However, the COVID-19 crisis has also created opportunities, such as the roll-out of teleconsultation and tele-expertise. The indicators described here as part of the monitoring system can help public decision-makers to become more responsive and to implement tailored actions to better meet the general population's healthcare needs.

[The impact of the COVID-19 pandemic on first-line primary care in southeastern France: Feedback on the implementation of a real-time monitoring system based on regional health insurance data]. / L'impact de l'épidémie de COVID-19 sur les soins de premier recours en région Provence-Alpes-Côte d'Azur : retour d'expérience sur la mise en place d'un dispositif de surveillance en temps réel à partir des données régionales de l'Assurance maladie.

BACKGROUND: Starting in spring 2020, the COVID-19 pandemic markedly impacted the French healthcare system. Lockdown and risks of exposure to the coronavirus induced patients to modify their ways of use. The objective of this article was to share feedback on the implementation of a real-time monitoring system concerning (a) the activity of private practitioners in southeastern France, and (b) the evolution of reimbursements for drugs prescribed to persons with diabetes, for treatment of mental health disorders, and for performance of some vaccines. METHODS: Data regarding 2019 and 2020 were extracted from regional health insurance databases. They were used to elaborate several indicators relative to the general health insurance scheme, which were calculated and updated each week, starting with week 2. RESULTS: We observed a drop in private physician activity during the lockdown (-23% for general practitioners; -46% for specialist doctors), followed by a return to a semblance of normalcy. Concomitantly, a boom in teleconsultations occurred: at the height of the crisis they represented 30% of medical acts. The initial stage of the lockdown was characterized by peak provisioning for drugs, whereas vaccination strongly declined (-39% regarding measles, mumps and rubella vaccine among children aged less than 5 years; -54% regarding human papillomavirus vaccine among girls aged 10 to 14 years). CONCLUSION: The COVID-19 pandemic could lead to health effects other than those directly attributable to the coronavirus itself. Renouncing care may result in healthcare delays highly deleterious for people and society. Public authorities are preoccupied with these questions; they have set up action plans aimed at encouraging patients to seek treatment without delay. That said, the COVID-19 pandemic crisis has also created opportunities, such as the expansion of telemedicine. Although partial, these indicators can provide useful information enabling public decision makers to be reactive and to implement specific actions to meet the health needs of the population.

Health care utilization by men with prostate cancer during the year before their death: A 2015 population-based study.

INTRODUCTION: To study the characteristics and health care utilization of men with prostate cancer (PCa) during their last year and last month of life, as these data have been rarely reported to date. SUBJECTS AND METHOD: Men covered by the national health Insurance general scheme (77% of the French population) treated for PCa (2014-2015), who died in 2015 were identified in the national health data system, including reimbursed hospital and outpatient care, and their causes of death. RESULTS: A total of 11,193 men (mean age: 81 years, SD: 9.6) were included. Almost 58% of these men died in a short-stay hospital (SSH), 4% died in hospital-at-home, 9% died in Rehab, 9% died in skilled nursing homes and 21% died at home. During the last year of life, almost all men were hospitalised at least once in SSH and 47% received hospital palliative care (HPC), immediately prior to death in 8% of cases. During the last month of life, 76% of men were hospitalised at least once in SSH, 43% attended an emergency department and 14% were admitted to intensive care, 7% received a chemotherapy session, and 24% received an antineoplastic agent dispensed by a retail pharmacy. Cancer was the main cause of death for 63% of men, corresponding to PCa in 40% of cases, and cardiovascular disease was the main cause of death for 13% of men with marked variations according to age, place of death, and use of HPC. The mean cost reimbursed per man during the last year of life was €38,750 (€48,601 including HPC). CONCLUSIONS: In France, end-of-life management of men with PCa, regardless of the cause of death, is centered on SSH and HPC, essentially at the time of death. Certain indicators of end-of-life management were particular high. LEVEL OF EVIDENCE: 4.

Kinetically Enhanced Fabrication of Homogeneous Biomimetic and Functional Emulsion Droplets.

Characterized by a fluid and deformable interface, ligand-functionalized emulsion droplets are used as model probes to address biophysical, biological, and developmental questions. Functionalization protocols usually rely on the use of headgroup-modified phospholipids that are dissolved in the oil phase prior to emulsification, leading to a broad range of surface densities within a given droplet population. With the aim to coat particles homogeneously with biologically relevant lipids and proteins (streptavidin, immunoglobulins, etc.), we developed a reliable surface decoration protocol based on the use of polar cosolvents to dissolve the lipids in the aqueous phase after the droplet production. We show that the surface density of the lipids at the interface has a narrow normal distribution for droplets having the same size. We performed titration isotherms for lipids and biologically relevant proteins on these drops. Then, we studied the influence of the presence of surfactants in the medium on lipid insertion and compared the results for a range of polar cosolvents of increasing polarity. To assess both the generality and the biocompatibility of the method, we show that we can produce more sophisticated, monodisperse functional magnetic emulsions with a very high surface homogeneity. Using an oil denser than the surrounding culture medium, we show that IgG-coated droplets can be used as probes for phagocytosis experiments.

Value of a national administrative database to guide public decisions: From the système national d'information interrégimes de l'Assurance Maladie (SNIIRAM) to the système national des données de santé (SNDS) in France.

In 1999, French legislators asked health insurance funds to develop a système national d'information interrégimes de l'Assurance Maladie (SNIIRAM) [national health insurance information system] in order to more precisely determine and evaluate health care utilization and health care expenditure of beneficiaries. These data, based on almost 66 million inhabitants in 2015, have already been the subject of numerous international publications on various topics: prevalence and incidence of diseases, patient care pathways, health status and health care utilization of specific populations, real-life use of drugs, assessment of adverse effects of drugs or other health care procedures, monitoring of national health insurance expenditure, etc. SNIIRAM comprises individual information on the sociodemographic and medical characteristics of beneficiaries and all hospital care and office medicine reimbursements, coded according to various systems. Access to data is controlled by permissions dependent on the type of data requested or used, their temporality and the researcher's status. In general, data can be analyzed by accredited agencies over a period covering the last three years plus the current year, and specific requests can be submitted to extract data over longer periods. A 1/97th random sample of SNIIRAM, the échantillon généraliste des bénéficiaires (EGB), representative of the national population of health insurance beneficiaries, was composed in 2005 to allow 20-year follow-up with facilitated access for medical research. The EGB is an open cohort, which includes new beneficiaries and newborn infants. SNIIRAM has continued to grow and extend to become, in 2016, the cornerstone of the future système national des données de santé (SNDS) [national health data system], which will gradually integrate new information (causes of death, social and medical data and complementary health insurance). In parallel, the modalities of data access and protection systems have also evolved. This article describes the SNIIRAM data warehouse and its transformation into SNDS, the data collected, the tools developed in order to facilitate data analysis, the limitations encountered, and changing access permissions.

[Health care use by free complementary health insurance coverage beneficiaries in France in 2012]. / Consommations de soins des bénéficiaires de la couverture maladie universelle complémentaire (CMUC) ou de l'aide pour une complémentaire santé (ACS) en 2012.

BACKGROUND: The objective was to investigate healthcare use among people covered by one of the two complementary healthcare insurance schemes available for people with low annual income: CMUC (universal complementary healthcare insurance) and, for people whose income exceeds the CMUC ceiling, ACS (aid for complementary healthcare insurance). Comparisons were made between CMUC and ACS beneficiaries versus CMUC and ACS non-beneficiaries and between CMUC beneficiaries and ACS beneficiaries. METHODS: Using the national health insurance information system (SNIIRAM), people less than 60 years old covered by the general national health insurance (86% of the 66 million inhabitants) and with ACS or CMUC coverage in 2012 were selected. Diseases were identified using hospital diagnosis, drugs refunds and long-term chronic disease status. Hospital related diagnoses were categorized in major hospital activity groups. Sex- and age-standardized relative risk (RR) were calculated. RESULTS: There were 4.4 million (9.6%) CMUC beneficiaries and 732,000 (1.6%) ACS beneficiaries (56% and 54% women; mean age: 24 years and 29 years respectively versus 52% and 30 years for CMUC or ACS non-beneficiaries). CMUC or ACS beneficiaries had more often cardiovascular diseases (RR=1.4;2.1) and diabetes (RR=2.2;2.4). Their sex- and age-standardized hospitalisation rates for all diagnosis were higher (18%; 17%, RR=1.3;1.4) than CMUC or ACS non-beneficiaries (13%). This was especially the case for the following major groups: toxicology, intoxications, alcohol major group (RR=3.8;4.0); psychiatry (RR=2.8;4.1); respiratory disease (RR=1.9;2.3); infectious disease (RR=1.9;2.7). Compared with CMUC beneficiaries, ACS beneficiaries had more often cancer (RR=1.5), cardiovascular disease (RR=1.5), neurological disease (RR=2.7), psychiatric illness (RR=2.6), end-stage renal disease (RR=2.8), hemophilia (RR=1.4) or cystic fibrosis (RR=1.6) and they received also more often disability allowance (20%, 4%). CONCLUSION: The disease and hospitalisation rates of ACS beneficiaries are similar or higher than those of CMUC beneficiaries, especially for disabling diseases. Both CMUC and ACS beneficiaries received healthcare for chronic diseases that can be targeted by prevention and screening programs for more optimal healthcare.

Design of magnetic molecularly imprinted polymer nanoparticles for controlled release of doxorubicin under an alternative magnetic field in athermal conditions.

An innovative magnetic delivery nanomaterial for triggered cancer therapy showing active control over drug release by using an alternative magnetic field is proposed. In vitro and In vivo release of doxorubicin (DOX) were investigated and showed a massive DOX release under an alternative magnetic field without temperature elevation of the medium.

[Mediterranean spotted fever in a 3-year-old child]. / Fièvre boutonneuse méditerranéenne chez un enfant de 3ans.

We report the case of a 3-year-old patient with Mediterranean spotted fever (MSF). The patient was infected through a tick bite in the forests surrounding Paris. Treatment with azithromycin was started with good results. MSF is not exceptional and should be considered in patients with fever, rash, and eruptions even outside the usual infested areas.

Surface decoration of catanionic vesicles with superparamagnetic iron oxide nanoparticles: a model system for triggered release under moderate temperature conditions.

We report the design of new catanionic vesicles decorated with iron oxide nanoparticles, which could be used as a model system to illustrate controlled delivery of small solutes under mild hyperthermia. Efficient release of fluorescent dye rhodamine 6G was observed when samples were exposed to an oscillating magnetic field. Our system provides direct evidence for reversible permeability upon magnetic stimulation.

[Zuclopenthixol benzoate poisoning in a child: evidence from chromatography]. / Intoxication au zuclopenthicol benzoate : mise en évidence par chromatographie.

Zuclopenthixol is a thioxanthene-based neuroleptic. It may cause acute intoxication in children with neurological and consciousness disorders. Immunochromatography is unable to identify the molecule and diagnosis requires mass spectroscopy and HP chromatography. The short time needed for this technique significantly improves the exploration and treatment of Clopixol(®) poisoning.

[Coronary embolism due to an adherent right atrium thrombus through a patent foramen ovale]. / Embolies coronaires secondaires à un thrombus adhérent de l'oreillette droite par un foramen ovale perméable.

This observation relates to the discovery of native coronary paradoxical embolism secondary to thrombus adherent to the right atrium through a patent foramen ovale (PFO). A patient of 64 years, with a history of mitral regurgitation not followed, was hospitalized for acute respiratory distress due to a mitral insufficiency (MI) with a ruptured chordae and pulmonary embolism. Coronary angiography was performed and revealed two typical images of coronary embolism associated to a non-atheromatous coronary tree. The patient underwent a mitral valve replacement. After the establishment of cardiopulmonary bypass, adherent fibrin and cruoric thrombus of the right atrium and a PFO were found. The analysis of the valves did not reveal any arguments for infective endocarditis. A CT scan, performed as the patient remained unconscious after surgery, showed several cerebral infarcts. Paradoxical embolism coronary was diagnosed in front of the combination of adherent thrombus in the right atrium, pulmonary embolism and systemic coronary and cerebral embolism with a PFO. Coronary embolism rarely happens. It is mainly due to three causes: iatrogenic origin in most cases, direct causes due to micro emboli, particularly from infectious endocarditis and paradoxical embolic origin. There are two types of right atrial thrombus; the most common is the mobile thrombus from the peripheral venous system. The other one, which is more rare, is the adherent thrombus, which occurs in situ. Coronary embolism of paradoxical origin represents a small proportion of the causes of coronary embolism. However, this diagnosis must be considered.

Severe clinical toxicities are correlated with survival in patients with advanced renal cell carcinoma treated with sunitinib and sorafenib.

BACKGROUND: In advanced renal cell carcinoma (RCC), sunitinib and sorafenib tyrosine kinase inhibitors (TKI) are associated with several clinical side effects, with no definitive established data concerning their clinical impact. METHODS: From June 2006 to June 2008, main clinical TKI-induced toxicities, including digestive, cardiac, dermatologic and asthenia were retrospectively collected using the NCI-CTC version 3.0 in patients treated with TKI for an RCC. RESULTS: The median overall survival was significantly improved in patients with grade 3-4 clinical toxicities (36 vs 12 months, P=0.009). In multivariate analysis, the Memorial Sloan-Kettering Cancer Center risk groups (good vs intermediate or poor) and clinical toxicities (grade 3-4 vs 1-2) were identified as independent prognostic factors of better survival (P=0.002 and P=0.02, respectively). The Charlson comorbidity index score (>7 vs <7) was identified as independent predictive factor of severe clinical TKI-induced toxicities (P=0.02). CONCLUSION: In this unselected patients of RCC, clinical TKI-related severe toxicities were more frequent in patients with comorbidities and were associated with better survival.

[Pneumococci isolated from vaccinated children with pneumonia]. / Pneumocoques isolés dans les pneumonies d'enfants vaccinés.

Among 76 children fully vaccinated with 7-valent conjugate vaccine and subsequently hospitalized from 2006 to 2009 for community-acquired pneumonia, isolated or with empyema or pleuritis, 10 had confirmed pneumococcal infections. All pneumococci isolated with blood or pleural culture were non vaccine serotypes (1, 5, 7F, and 19A). The proportion of pneumococcal pneumonias was similar to that in two series from the same hospital before the vaccine era. These data show that the 13-valent conjugate vaccine could be useful in prevention of community-acquired pneumonia and that bacteriologic survey of community-acquired pneumonia remains necessary.

[Linezolide in paediatrics]. / Le linézolide en pédiatrie.

The spread of multiresistant Gram positive bacteria required the development of new drugs. Linezolid, a new oxazolidinone, is active against these pathogens and is marketed for the treatment of severe glycopeptides-resistant Gram positive-bacteria in adults. Moreover, the availability of intravenous and oral formulation with an excellent bioavailability of the latter, is hoped to facilitate the management of these infections. Most information regarding the pharmacoketic profile, efficacy and tolerability of linezolid in pediatric derived from adults studies. In this review we summarize evidence regarding the uses of linezolid in children focusing on the clinical efficacy data and safety in serious Gram-positive infections and also in compassional uses.

Acute osteomyelitis in children: the pathogenesis revisited?

PURPOSE OF THE STUDY: The present study reviews our experience of acute hematogenous osteomyelitis in 450 children over a period of 20 years from 1985 to 2004 at the Nouméa Territorial Hospital in New Caledonia. The objective was to formulate a new theory of the pathogenesis of this affection and to report our research on the disparity in the pathology between temperate countries and our own tropical Pacific area. PATIENT AND METHODS: Only children with an initially normal X-ray and showing symptoms for less than one week were included in the study. Subacute osteomyelitis, infant osteoarthritis and spinal and sacroiliac joint infections were all excluded. All children were treated according to a preestablished protocol including: clinical examination; blood tests; ultrasound, to determine the presence and size of the periosteal elevation and to exclude soft tissue abscess and frequent pyomyositis. Ultrasound was used in the decision to treat with antibiotics alone or with surgery. Computed Tomography was used for deep structures assessment and medical therapy guidance Surgery was limited to open drainage of the subperiosteal abscess only. Regular follow-up of outpatients was continued until normal blood test and X-ray results were achieved. RESULTS AND DISCUSSION: Four hundred and fifty children with a diagnosis of acute hematogenous osteomyelitis were identified, giving an average incidence of 22 new cases per year (range, 12-35). This incidence was two to five times as high as found in Europe. Fifty-three percent of our cases required surgical drainage (vs. 20 % in Europe). Ethnically, 60 % of the children were Melanesian and 20 % Polynesian (both represented less than 50 % of the local population). A similar incidence, about four times as high as in the population of European descent, was reported in Polynesians by our neighbors in New Zealand. The limbs were affected in 90 % of cases, and specifically lower limbs in 70 %. Multiple osseous lesions and systemic infection were recorded in 43 children (9.5 %). Blood cultures and surgical samples were positive in 80 % of cases, and otherwise negative. All the children were successfully treated, without chronic evolution or sequelae needing secondary surgery. The predominant microorganisms isolated were Staphylococcus aureus, in 81 % of cases, none of which were methicillin-resistant, and group A Streptococcus in 7.5 % of cases. A previous study of soft-tissue S. aureus infection showed the presence of Panton-Valentine Leukocidin (PVL) genes in 89 % of cases. These very infrequent genes are responsible for leukotoxic apoptosis, producing leukocidin, causing local acute aggressiveness. A parallel study, in progress for more than a year, is focusing on detecting PVL genes in S. aureus isolated from acute osteomyelitis: in the first nine children analyzed, PVL genes were likewise detected in 89 % of the S. aureus isolated, with no methicillin resistance. Ultrasonography allowed positive diagnosis in 64 % of cases on the day of admission and 84 % by the second day. Because of this very early presence of subperiosteal abscess at the beginning of the disease, and several other issues raised in the present study, we believe that Trueta's theory of acute osteomyelitis pathogenesis does not provide any logical explanation for our anatomoclinical observations. We believe that the primary focus of infection is in the osteoperiosteal area rather than under the growth plate in the metaphyseal bone. The term of Acute Osteo-Periostitis would therefore be much more suitable. A history of blunt trauma was found in 63 % of cases in the present series, and often reported in the literature. We speculate that two forms of infection fixation may develop: a local form, where bacteria carried by the blood stream reach a subperiosteal edema or hematoma secondary to blunt trauma, which is in our opinion the most frequent cause; and a general form, where fixation occurs as single or multifocal osteoperiostitis, and multivisceral locations in severe forms of septicemia. The disparity in this pathology between temperate countries and our own tropical Pacific area is certainly due to PVL-positive S. aureus and ethnic factors. The high prevalence of Melanesian and Polynesian patients confirms that they are at high risk of musculoskeletal infection in New Caledonia as in other Pacific countries, and it is possible that these ethnic groups are genetically susceptible to PVL-positive strains. LEVEL OF EVIDENCE: Level IV. Retrospective case series.

Knowledge, attitudes and vaccination coverage of healthcare workers regarding occupational vaccinations.

OBJECTIVES: Immunization of healthcare workers (HCWs) is a major issue for infection control in healthcare facilities. The aim of this study was to evaluate knowledge regarding occupational vaccinations, HBV, varicella and influenza vaccination rates and attitudes towards influenza vaccine among HCWs. DESIGN AND SETTING: A cross-sectional survey was conducted in two wards (Medicine and Paediatrics) of a 1182-bed teaching hospital in Paris, France. METHODS: A standardized, anonymous, self-administered questionnaire was used. RESULTS: Of 580 HCWs, 395 (68%) completed the questionnaire. Knowledge about the occupational vaccinations of HCWs was low. HBV (69%), tuberculosis (54%) and influenza (52%) were the most cited vaccinations. Paediatric staff was more aware of influenza and pertussis immunizations (p<.05). HBV vaccination rate was 93%, among whom 65% were aware of their immune status. Influenza vaccination rate for 2006-2007 was 30% overall, ranging from 50% among physicians to 20% among paramedical staff (p<.05). Physicians based their refusal on doubts about vaccine efficacy, although paramedics feared side effects. Influenza vaccination was associated with knowledge of vaccine recommendations [OR=1.75, 95% CI: 1.13-2.57] and contact with patients [OR=3.05, 95% CI: 1.50-5.91]. CONCLUSIONS: Knowledge of recommended occupational vaccinations is insufficient in HCWs, except for HBV and influenza. Although the HBV vaccine coverage of HCWs is satisfactory, a large proportion of them is unaware of immune status. Influenza vaccine coverage remains low, especially among paramedical staff because of fear of side effects. As vaccine coverage is associated with knowledge, educational campaigns should be strengthened to increase the adhesion of HCWs to vaccinations.