A yellow fever-Zika chimeric virus vaccine candidate protects against Zika infection and congenital malformations in mice.

The recent Zika virus (ZIKV) epidemic in the Americas led to an intense search for therapeutics and vaccines. Here we report the engineering of a chimeric virus vaccine candidate (YF-ZIKprM/E) by replacing the antigenic surface glycoproteins and the capsid anchor of YFV-17D with those of a prototypic Asian lineage ZIKV isolate. By intracellular passaging, a variant with adaptive mutations in the E protein was obtained. Unlike YFV-17D, YF-ZIKprM/E replicates poorly in mosquito cells. Also, YF-ZIKprM/E does not cause disease nor mortality in interferon α/ß, and γ receptor KO AG129 mice nor following intracranial inoculation of BALB/c pups. A single dose as low as 1 × 102 PFU results, as early as 7 days post vaccination, in seroconversion to neutralizing antibodies and confers full protection in AG129 mice against stringent challenge with a lethal inoculum (105 LD50) of either homologous or heterologous ZIKV strains. Induction of multi-functional CD4+ and CD8+ T cell responses against ZIKV structural and YFV-17D non-structural proteins indicates that cellular immunity may also contribute to protection. Vaccine immunogenicity and protection was confirmed in other mouse strains, including after temporal blockade of interferon-receptors in wild-type mice to facilitate ZIKV replication. Vaccination of wild-type NMRI dams with YF-ZIKprM/E results in complete protection of foetuses against brain infections and malformations following a stringent intraplacental challenge with an epidemic ZIKV strain. The particular characteristic of YF-ZIKprM/E in terms of efficacy and its marked attenuation in mice warrants further exploration as a vaccine candidate.

A Single-Dose Live-Attenuated Zika Virus Vaccine with Controlled Infection Rounds that Protects against Vertical Transmission.

Zika virus (ZIKV) infection of the mother during pregnancy causes devastating Zika congenital syndrome in the offspring. A ZIKV vaccine with optimal safety and immunogenicity for use in pregnant women is critically needed. Toward this goal, we have developed a single-dose live-attenuated vaccine candidate that infects cells with controlled, limited infection rounds. The vaccine contains a 9-amino-acid deletion in the viral capsid protein and replicates to titers of > 106 focus-forming units (FFU)/mL in cells expressing the full-length capsid protein. Immunization of A129 mice with one dose (105 FFU) did not produce viremia, but elicited protective immunity that completely prevented viremia, morbidity, and mortality after challenge with an epidemic ZIKV strain (106 PFU). A single-dose vaccination also fully prevented infection of pregnant mice and maternal-to-fetal transmission. Intracranial injection of the vaccine (104 FFU) to 1-day-old mice did not cause any disease or death, underscoring the safety of this vaccine candidate.

GREFON recommendations for assessment of instrumental activities of daily living in memory clinics.

Following a review of the available assessment scales and current practices of evaluation of instrumental activities of daily living (IADL) in French memory centres by GREFON (Groupe de réflexion sur l'évaluation fonctionnelle; Working Group on Functional Assessment), the main aim of this position paper was to provide good clinical practice (GCP) guidelines for the assessment of IADL. Another aim was to highlight the need for innovative tools adapted to the present and future evolution of such activities in real life, including the use of new technologies, the need for earlier detection of IADL impairment during the diagnostic process of mild neurocognitive disorders, and greater sensitivity to IADL changes during follow-up to allow adaptation of clinical management and evaluation of the impact of therapeutic interventions.

Utility of 123I-FP-CIT SPECT for dementia diagnoses and therapeutic strategies in elderly patients.

OBJECTIVES: Evaluation of the influence of single photon emission computed tomography (SPECT) of the dopamine transporter (123I-FP-CIT) on diagnosis and treatment strategies in elderly patients with mild dementia. DESIGN: Retrospective study. SETTING: Geriatrics memory clinic. PARTICIPANTS: Consecutive ambulatory patients who had 123I-FP-CIT SPECT for a suspicion of DLB. MEASUREMENTS: Clinical diagnoses before SPECT were compared with imaging results. RESULTS: 46 patients were included. Pre imaging clinical hypotheses were probable DLB in 14, possible DLB in 21 and alternate diagnoses in 11. Rates of abnormal imaging in these groups were respectively 71%, 43% and 18%. Overall, diagnoses were revised in 37% of the cases. Four patients with probable DLB had normal imaging. Their number of core criteria did not differ from the remainder (2.75 ± 0.5 vs. 2.1 ± 0.6), but hallucinations in 2 patients were not well formed and detailed as usual in DLB. Among 38 patients free of antipsychotics, rates of abnormal scans were 36% in patients with questionable parkinsonism, 57% in definite parkinsonism, 67% in patients with no parkinsonism. Among 9 patients on Levodopa, 6 had normal scans and Levodopa was stopped. CONCLUSION: We show a significant impact of 123I-FP-CIT SPECT on diagnoses, even in cases of definite parkinsonism or probable DLB. In the latter, scarcity of hallucinations, especially if there are not well formed and detailed, should prompt 123I-FP-CIT SPECT.

[Medical comorbidity in Alzheimer's disease: baseline characteristics of the REAL.FR Cohort]. / Comorbidités et maladie d'Alzheimer: données à l'inclusion de la cohorte gériatrique REAL.FR.

PURPOSE: Alzheimer's disease (AD) evolves over about ten years with cognitive decline that can be considered as linear. Comorbidities are frequent in geriatric population. The major objective of this study is to determine whether comorbidity influences natural history of AD. MATERIALS AND METHODS: This is a prospective, multicentric French study (REAL.FR) of a cohort of ambulatory patients suffering from AD from a mild to a moderately severe stage, with a Mini-Mental State between 10 and 26, and followed with a caregiver. We evaluated the comorbidities and they were quantified using the Charlson index. RESULTS: We analysed 579 AD patients enrolled between April 2000 and June 2002. Majority of patients were women (72%). Average age and MMS average score were respectively 77.4 +/- 7.1 and 20.1 +/- 4.5. Cardiovascular diseases were the most frequent comorbid conditions (34%), before sensorial handicap (23%), and neurological diseases (18%) apart from dementia. Four AD patients groups differed according to the comorbidities figures, from none to more than three (maximum 8). Average Charlson index was 1.5 +/- 0.9. CONCLUSION: The follow-up of the four AD patients groups, differentiated by the comorbidities figures, should allow to precise the influence of comorbidities on the AD evolution. Charlson index could be used to quantify the comorbidities in the cohort's follow-up. However, this index, validated in a cohort of cancer patients, show limits for its use in geriatric population.

Role of behavioural disturbance in the loss of autonomy for activities of daily living in Alzheimer patients.

BACKGROUND: Cognitive impairment is associated with functional impairment in patients with Alzheimer's disease (AD). Behavioural disturbance is very common in these patients. Nevertheless, there has been very little research into the relations between behavioural disturbance and functional status in AD. The purpose of this study is to investigate the relationship between behavioural disturbance and functional status after taking account of cognitive impairment. MATERIAL AND METHODS: 579 patients were prospectively evaluated at 16 French hospitals, all referents for AD, and were diagnosed with possible or probable AD. These patients were assessed with NeuroPsychiatric Inventory (NPI), cognitive subscales of the Alzheimer's Disease Assessment Scale (ADAS-cog), Clinical Dementia Rating scale (CDR) and Instrumental Activities of Daily Living scale (IADL). RESULTS: The number of men with available data for IADL total score was too small to make any analysis. 'Group A' gathered 256 women for whom the relation between autonomy for Activities of Daily Living (ADL) and the other variables were determined. 'Group B', pooled 85 women for whom relations found were verified. Linear regression was used for the analysis. With age, cognitive impairment allows us to explain best (38%) the loss of autonomy for ADL. CONCLUSION: The role of behavioural disturbances in the loss of autonomy for ADL was not determinant in our study, whereas cognitive impairment and age were better able to determine the loss of autonomy for ADL. Further study is needed to explain the decline of functional status in AD patients.

[Clinical features of ambulatory patients over 80 years of age followed for Alzheimer's disease. French prospective multicenter study REAL.FR]. / Caractéristiques cliniques des patients ambulatoires âgés de plus de 80 ans suivis pour une maladie d'Alzheimer. Etude française multicentrique prospective REAL.FR.

PURPOSE: Twice out off three, patients with Alzheimer's disease (AD) are aged 80 and older. Very old patients are more frail, have social precariousness and have often polypathology. Few data are available about these elderly patients. The aim of our study was to analyse characteristics of AD patients aged 80 and older. MATERIAL AND METHODS: This is a prospective, multicentric French study (REAL.FR) of a cohort of ambulatory AD patients, with Mini-Mental State values between 10 and 26. Clinical and social data at inclusion of patients aged 80 and older and patients younger were compared. RESULTS: Six hundred eighty nine patients (488 women, 201 men) were included between April 2000 and June 2002. The mean age was 77.8 +/- 6.9 years. Two hundred sixty four patients (38%) were aged 80 and older. Those patients were more dependant for Activities of Daily Living (ADL) than younger patients (ADL score of Katz: 5.2 +/- 1.07 et 5.6 +/- 0.74 respectively; p < 0.001 and IADL (Instrumental Activities of Daily Living) score of Lawton: 7.3 +/- 3.57 et 9.3 +/- 1.57 respectively; p < 0.001). Duration of evolution of the disease were comparable between older and younger patients. CONCLUSION: In our cohort, AD patients aged 80 and older had a weakest autonomy for the ADL than younger patients with the same stage of the disease. Results has implications on care. Following the cohort will permit to specify evolution of data.

The application of the theoretical model WHO/FDI planning system to an industrialised country: France.

The results of the application of the WHO/FDI planning system to a specific situation in an industrialised country provide valid arguments in favour of its use. It is shown to be an aid to planners when estimating oral health personnel requirements and emphasises the necessity of obtaining basic information on the oral health status and demand for treatment in industrialised countries. The strength of the system lies in the fact that it enables the user to forecast requirements, by age cohort and by type of care, while at the same time including socio-economic variables which have a major influence in industrialised countries with moderate caries levels. This flexibility of use enables the system to be adapted, if necessary, or even improved, according to the constraints which may result from a specific situation analysis.