[Non-donor patients' opinions about general practitioners' influence on first blood donation]. / Influence du médecin généraliste dans la promotion du primo-don du sang selon les patients.

BACKGROUND: Needs for labile blood products are continuously increasing in France. National self-sufficiency is currently achieved because important promotional efforts for blood donation have resulted in more than three million donations per year. Despite the peculiar relationship general practitioners (GPs) have with every patient and with public health actions, GPs are not included in the blood donation promotion chain. In this study, the main goal was to determine, from a non-donor patient's point of view, whether a discussion with their GP could be an efficient tool in blood donation promotion. The study was also designed to identify barriers to donation and information patients would expect from their GPs in such a discussion. METHODS: This was an epidemiological analytical cross-sectional and multicenter study. All patients aged 18 to 70 years attending a GP's clinic in Nord-Pas-de-Calais was asked to complete a seven-item closed-question survey. The primary endpoint was the percentage of patients who stated that the discussion with their GP could be an efficient tool for promoting blood donation. RESULTS: One thousand and forty-eight surveys were included in the analysis. Four hundred and fifty of the 660 non-donors interviewed (68.2 %) declared that a discussion with their GP could encourage them in the blood donation process. Non-donors declared that lack of time was the main barrier (33.5 %) and that they expected information from their GP about when and where they could donate blood (40.3 %). CONCLUSION: Many non-donor patients attending primary care clinics declare that a discussion with their GP could encourage them to make a blood donation and therefore significantly increase the number of potential donors.

Explicit definitions of potentially inappropriate prescriptions of antibiotics in hospitalized older patients.

CONTEXT: The use of explicit definitions of potentially inappropriate prescriptions of antibiotics (antibiotic PIPs) might constitute an innovative means to fight against antimicrobial resistance. Explicit definitions of PIPs can reduce the rate of inappropriate prescriptions, but explicit definitions of antibiotic PIPs in geriatric medicine are currently lacking. The objective of the study was to develop explicit definitions of antibiotic PIPs for hospitalized older patients. METHOD: We performed a qualitative study of focus groups involving geriatricians and infectious disease specialists. The study complied with the Consolidated Criteria for Reporting Qualitative Research. Transcripts of audio recordings were analyzed in a two-step independent reviewing process. The exact wording of the definitions was validated by a steering committee, an independent expert group, and the focus group participants. RESULTS: The four focus groups comprised 28 stakeholders. Our analysis identified 65 explicit definitions of antibiotic PIPs: 47 (73%) concerned misuse, 15 (23%) concerned overuse and three (5%) concerned underuse. Most definitions were related to critically important antibiotics: 11 (17%) for fluoroquinolones, eight (12%) for amoxicillin-clavulanic acid, eight (12%) for cephalosporins, seven (11%) for aminoglycosides, and five (8%) for carbapenems. CONCLUSION: To address the public health challenge of antimicrobial resistance, our study generated explicit definitions for antibiotic PIPs in older patients. We intend to refine and to validate these definitions through a national Delphi survey; the resulting consensus might provide key messages for prescribers and open up perspectives for reducing the incidence of antibiotic PIPs.

The Care Coordinator's Tasks During the Implementation of an Integrated Care Pathway for Older Patients: A Qualitative Study Based on the French National "Health Pathway of Seniors for Preserved Autonomy" Pilot Program.

Background: Although integrated care and care coordination are known to be beneficial for older adults' population, the specific tasks of a Care Coordinator (CC) for integrated care pathways for this population have not been studied in detail. Setting & Subjects: The French national pilot program PAERPA provided an integrated care pathway for older adults. In North France, a CC was recruited to support patients and professionals. Objectives: (i) To analyse the CC's tasks in an integrated care pathway for older patients, and (ii) to record perceptions on the CC's tasks among the participating general practitioners (GP) and community pharmacists. Design & Methods: Qualitative, two-phase study: (i) Task analysis of the CC's tasks, to compare the planned and actual tasks; (ii) semi-structured interviews among GPs and community pharmacists involved in the pathway. Results: (i) The task analysis showed that the CC's actual tasks differed from planned tasks. The CC was only meant to be involved in the early stages of the process; actually, the CC undertook more or even unforeseen tasks in coordination, communication, and administrative support throughout the care pathways. (ii) The 28 interviewed healthcare professionals considered the CC's tasks to be essential to the success of pathways. They appreciated the CC's administrative support. However, CC's tasks related to interprofessional communication, and patient and family information, were controversially perceived among GPs and pharmacists. Conclusions: The CC's tasks in an integrated care pathway for older adults showed that the CC's overall workload was greater than expected and appreciated by healthcare professionals.

[Changes in blood pressure after introduction of an antidepressant in a public institution of mental health]. / Évolution de la pression artérielle après introduction d'un antidépresseur en établissement public de santé mentale.

INTRODUCTION: Primary prescribing of antidepressants is common in general practice. The relationship between antidepressant introduction and blood pressure (BP) changes is not well established in the literature. The purpose of our study was to examine the short-term course of AHR with and without the introduction of an antidepressant into a public institution of mental health (EPSM). MATERIALS AND METHODS: An exposed/non-exposed single-centre analytical epidemiological study on a retrospective cohort, with a collection of data on stays between 2013 and 2015 at the EPSM in Armentières. The stays were divided into two groups: antidepressant treatment (introduced during the stay) and control (without antidepressant). BP measurements were taken over a 30-day period per stay. To assess the evolution of AHR across groups, we used a nested mixed linear regression model with multivariate adjustment. RESULTS: Out of 1241 stays analysed, 124 were in the treated group and 1117 in the control group. The average age was 44.6±14.7 years. The two groups were comparable on most of the variables analyzed. The change in systolic BP was associated with systolic BP values at baseline, history of hypertension, presence of an antihypertensive drug and BMI; the change in diastolic BP was associated with diastolic BP values at baseline, presence of an antihypertensive drug, BMI and history of bipolar disorder. We find no significant difference in the evolution of BP over time between the treated group and the control group over the 30 days of measurement per stay, after adjustment (evolution coefficient of +0.12mmHg systolic BP and -0.1mmHg diastolic BP, P=0.45 and 0.38 respectively). CONCLUSION: These results are reassuring on the early development of BP after the introduction of antidepressants. They should not overlook the frequent effects of depression and antidepressants on cardiovascular risk (decreased physical activity, dyslipidemia, weight gain, etc.).

T cell-derived interferon-γ programs stem cell death in immune-mediated intestinal damage.

Despite the importance of intestinal stem cells (ISCs) for epithelial maintenance, there is limited understanding of how immune-mediated damage affects ISCs and their niche. We found that stem cell compartment injury is a shared feature of both alloreactive and autoreactive intestinal immunopathology, reducing ISCs and impairing their recovery in T cell-mediated injury models. Although imaging revealed few T cells near the stem cell compartment in healthy mice, donor T cells infiltrating the intestinal mucosa after allogeneic bone marrow transplantation (BMT) primarily localized to the crypt region lamina propria. Further modeling with ex vivo epithelial cultures indicated ISC depletion and impaired human as well as murine organoid survival upon coculture with activated T cells, and screening of effector pathways identified interferon-γ (IFNγ) as a principal mediator of ISC compartment damage. IFNγ induced JAK1- and STAT1-dependent toxicity, initiating a proapoptotic gene expression program and stem cell death. BMT with IFNγ-deficient donor T cells, with recipients lacking the IFNγ receptor (IFNγR) specifically in the intestinal epithelium, and with pharmacologic inhibition of JAK signaling all resulted in protection of the stem cell compartment. In addition, epithelial cultures with Paneth cell-deficient organoids, IFNγR-deficient Paneth cells, IFNγR-deficient ISCs, and purified stem cell colonies all indicated direct targeting of the ISCs that was not dependent on injury to the Paneth cell niche. Dysregulated T cell activation and IFNγ production are thus potent mediators of ISC injury, and blockade of JAK/STAT signaling within target tissue stem cells can prevent this T cell-mediated pathology.

The cell cycle molecules behind neurodegeneration in Alzheimer's disease: perspectives for drug development.

Alzheimer's disease (AD), the leading cause of senile dementia, has become a considerable social and economical problem. Current AD therapeutics provide mainly symptomatic short-term benefit, rather than targeting disease mechanisms. The hallmarks for AD are beta-amyloid plaques, neurofibrillary tangles, and regionalized neuronal loss. Additional neuropathological features have been described that may provide some clues to the mechanism by which neurons die in AD. Specifically, the aberrant expression of cell cycle proteins and the presence of de novo-replicated DNA in neurons have been described both in AD brain and in culture models of the disease. The unscheduled cell cycle events are deleterious to neurons, which undergo death rather than complete the cell cycle. Although our understanding of the neuronal cell cycle is not complete, experimental evidence suggests that compounds able of arresting the aberrant cell cycle will yield neuroprotection. This review focuses on drug development centered on the cell cycle hypothesis of AD.

Progenitor cells from the adult mouse brain acquire a neuronal phenotype in response to beta-amyloid.

Neurospheres from adult mouse subventricular zone (SVZ) were grown in suspension cultures for 12-15 days. Neurospheres consisted mainly of neural precursor cells (NPCs) immunoreactive for nestin and also contained nestin-negative precursors. We used these neurospheres to determine the effects of synthetic beta-amyloid fragments (both betaAP(1-42) and betaAP(25-35)) on NPC proliferation, differentiation and survival. We show that neurospheres exposed to 25 microM betaAP(25-35) or betaAP(1-42) for 24 h (a toxic condition for mature neurons) did not undergo apoptosis. Instead, betaAP(25-35) orientated nestin-negative precursors towards nestin-positive NPCs and turned nestin-positive NPCs into neuroblasts. Intracerebroventricular infusion of full-length betaAP(1-42) increased the population of PSA-NCAM-positive cells in the SVZ, without affecting proliferation. We conclude that betaAP influences the fate of progenitor cells, driving their differentiation towards a neuronal lineage.

Clonal B cells in Waldenström's macroglobulinemia exhibit functional features of chronic active B-cell receptor signaling.

Waldenström's macroglobulinemia (WM) is a B-cell non-Hodgkin's lymphoma (B-NHL) characterized by immunoglobulin M (IgM) monoclonal gammopathy and the medullary expansion of clonal lymphoplasmacytic cells. Neoplastic transformation has been partially attributed to hyperactive MYD88 signaling, secondary to the MYD88 L265P mutation, occurring in the majority of WM patients. Nevertheless, the presence of chronic active B-cell receptor (BCR) signaling, a feature of multiple IgM+ B-NHL, remains a subject of speculation in WM. Here, we interrogated the BCR signaling capacity of primary WM cells by utilizing multiparametric phosphoflow cytometry and found heightened basal phosphorylation of BCR-related signaling proteins, and augmented phosphoresponses on surface IgM (sIgM) crosslinking, compared with normal B cells. In support of those findings we observed high sIgM expression and loss of phosphatase activity in WM cells, which could both lead to signaling potentiation in clonal cells. Finally, led by the high-signaling heterogeneity among WM samples, we generated patient-specific phosphosignatures, which subclassified patients into a 'high' and a 'healthy-like' signaling group, with the second corresponding to patients with a more indolent clinical phenotype. These findings support the presence of chronic active BCR signaling in WM while providing a link between differential BCR signaling utilization and distinct clinical WM subgroups.