Apical size and deltaA expression predict adult neural stem cell decisions along lineage progression.

The maintenance of neural stem cells (NSCs) in the adult brain depends on their activation frequency and division mode. Using long-term intravital imaging of NSCs in the zebrafish adult telencephalon, we reveal that apical surface area and expression of the Notch ligand DeltaA predict these NSC decisions. deltaA-negative NSCs constitute a bona fide self-renewing NSC pool and systematically engage in asymmetric divisions generating a self-renewing deltaAneg daughter, which regains the size and behavior of its mother, and a neurogenic deltaApos daughter, eventually engaged in neuronal production following further quiescence-division phases. Pharmacological and genetic manipulations of Notch, DeltaA, and apical size further show that the prediction of activation frequency by apical size and the asymmetric divisions of deltaAneg NSCs are functionally independent of Notch. These results provide dynamic qualitative and quantitative readouts of NSC lineage progression in vivo and support a hierarchical organization of NSCs in differently fated subpopulations.

Inappropriate antibiotic prescribing and its determinants among outpatient children in 3 low- and middle-income countries: A multicentric community-based cohort study.

BACKGROUND: Antibiotic resistance is a global public health issue, particularly in low- and middle-income countries (LMICs), where antibiotics required to treat resistant infections are not affordable. LMICs also bear a disproportionately high burden of bacterial diseases, particularly among children, and resistance jeopardizes progress made in these areas. Although outpatient antibiotic use is a major driver of antibiotic resistance, data on inappropriate antibiotic prescribing in LMICs are scarce at the community level, where the majority of prescribing occurs. Here, we aimed to characterize inappropriate antibiotic prescribing among young outpatient children and to identify its determinants in 3 LMICs. METHODS AND FINDINGS: We used data from a prospective, community-based mother-and-child cohort (BIRDY, 2012 to 2018) conducted across urban and rural sites in Madagascar, Senegal, and Cambodia. Children were included at birth and followed-up for 3 to 24 months. Data from all outpatient consultations and antibiotics prescriptions were recorded. We defined inappropriate prescriptions as antibiotics prescribed for a health event determined not to require antibiotic therapy (antibiotic duration, dosage, and formulation were not considered). Antibiotic appropriateness was determined a posteriori using a classification algorithm developed according to international clinical guidelines. We used mixed logistic analyses to investigate risk factors for antibiotic prescription during consultations in which children were determined not to require antibiotics. Among the 2,719 children included in this analysis, there were 11,762 outpatient consultations over the follow-up period, of which 3,448 resulted in antibiotic prescription. Overall, 76.5% of consultations resulting in antibiotic prescription were determined not to require antibiotics, ranging from 71.5% in Madagascar to 83.3% in Cambodia. Among the 10,416 consultations (88.6%) determined not to require antibiotic therapy, 25.3% (n = 2,639) nonetheless resulted in antibiotic prescription. This proportion was much lower in Madagascar (15.6%) than in Cambodia (57.0%) or Senegal (57.2%) (p < 0.001). Among the consultations determined not to require antibiotics, in both Cambodia and Madagascar the diagnoses accounting for the greatest absolute share of inappropriate prescribing were rhinopharyngitis (59.0% of associated consultations in Cambodia, 7.9% in Madagascar) and gastroenteritis without evidence of blood in the stool (61.6% and 24.6%, respectively). In Senegal, uncomplicated bronchiolitis accounted for the greatest number of inappropriate prescriptions (84.4% of associated consultations). Across all inappropriate prescriptions, the most frequently prescribed antibiotic was amoxicillin in Cambodia and Madagascar (42.1% and 29.2%, respectively) and cefixime in Senegal (31.2%). Covariates associated with an increased risk of inappropriate prescription include patient age greater than 3 months (adjusted odds ratios (aOR) with 95% confidence interval (95% CI) ranged across countries from 1.91 [1.63, 2.25] to 5.25 [3.85, 7.15], p < 0.001) and living in rural as opposed to urban settings (aOR ranged across countries from 1.83 [1.57, 2.14] to 4.40 [2.34, 8.28], p < 0.001). Diagnosis with a higher severity score was also associated with an increased risk of inappropriate prescription (aOR = 2.00 [1.75, 2.30] for moderately severe, 3.10 [2.47, 3.91] for most severe, p < 0.001), as was consultation during the rainy season (aOR = 1.32 [1.19, 1.47], p < 0.001). The main limitation of our study is the lack of bacteriological documentation, which may have resulted in some diagnosis misclassification and possible overestimation of inappropriate antibiotic prescription. CONCLUSION: In this study, we observed extensive inappropriate antibiotic prescribing among pediatric outpatients in Madagascar, Senegal, and Cambodia. Despite great intercountry heterogeneity in prescribing practices, we identified common risk factors for inappropriate prescription. This underscores the importance of implementing local programs to optimize antibiotic prescribing at the community level in LMICs.

Outpatient antibiotic use attributable to viral acute lower respiratory tract infections during the cold season in France, 2010-2017.

Antibiotic stewardship requires clear insight into antibiotic overuse and the syndromes that lead to prescription. The aim of this study was to estimate the proportion of antibiotic prescriptions attributable to acute lower respiratory tract infections (LRTIs) during the cold season. Using individual data from the French National Health Insurance (NHI) database, weekly time series were constructed of outpatient antibiotic (beta-lactams and macrolides) prescriptions between January 2010 and December 2017. Time series were also constructed of tenth edition of the International Classification of Diseases (ICD-10) discharge diagnoses from a national network of emergency departments (EDs), stratified by specific syndromes (pneumonia, bronchitis, bronchiolitis and influenza-like illness). The number of outpatient antibiotic prescriptions attributable to these syndromes during the cold season in France was modeled and estimated for the entire population, young children (≤5 years) and the elderly (≥75 years). LRTIs accounted for 40% (95% confidence interval [95% CI]: 29, 52) of outpatient antibiotic use during the cold season for the entire population, including 23% (95% CI: 13, 33) and 17% (95% CI: 13, 22) for bacterial and viral infections, respectively. In children and the elderly, viral LRTIs were the reason for 38% (95% CI: 31, 46) and 20% (95% CI: 16, 25) of outpatient antibiotic use, respectively (with bronchiolitis accountable for half of use in young children). In the entire population and in children, respectively, outpatient antibiotic overuse attributable to viral LRTIs was estimated to be 289 (95% CI: 221, 374) and 1588 (95% CI: 1295, 1922) prescriptions per 100 000 inhabitants per week. These results highlight the major role of viral infections in driving antibiotic prescriptions, particularly in young children.

Dynamic spatiotemporal coordination of neural stem cell fate decisions occurs through local feedback in the adult vertebrate brain.

Neural stem cell (NSC) populations persist in the adult vertebrate brain over a lifetime, and their homeostasis is controlled at the population level through unknown mechanisms. Here, we combine dynamic imaging of entire NSC populations in their in vivo niche over several weeks with pharmacological manipulations, mathematical modeling, and spatial statistics and demonstrate that NSCs use spatiotemporally resolved local feedback signals to coordinate their decision to divide in adult zebrafish brains. These involve Notch-mediated short-range inhibition from transient neural progenitors and a dispersion effect from the dividing NSCs themselves exerted with a delay of 9-12 days. Simulations from a stochastic NSC lattice model capturing these interactions demonstrate that these signals are linked by lineage progression and control the spatiotemporal distribution of output neurons. These results highlight how local and temporally delayed interactions occurring between brain germinal cells generate self-propagating dynamics that maintain NSC population homeostasis and coordinate specific spatiotemporal correlations.

Association of Pneumococcal Conjugate Vaccine Coverage With Pneumococcal Meningitis: An Analysis of French Administrative Areas, 2001-2016.

Geographic variations of invasive pneumococcal disease incidence and serotype distributions were observed after pneumococcal conjugate vaccine introduction at regional levels and among French administrative areas. The variations could be related to regional vaccine coverage (VC) variations that might have direct consequences for vaccination-policy impact on invasive pneumococcal disease, particularly pneumococcal meningitis (PM) incidence. We assessed vaccine impact from 2001 to 2016 in France by estimating the contribution of regional VC differences to variations of annual local PM incidence. Using a mixed-effect Poisson model, we showed that, despite some variations of VC among administrative areas, vaccine impact on vaccine-serotype PM was homogeneously confirmed among administrative areas. Compared with the prevaccine era, the cumulative VC impact on vaccine serotypes led, in 2016, to PM reductions ranging among regions from 87% (25th percentile) to 91% (75th percentile) for 7-valent pneumococcal conjugate vaccine serotypes and from 58% to 63% for the 6 additional 13-valent pneumococcal conjugate vaccine serotypes. Nonvaccine-serotype PM increases from the prevaccine era ranged among areas from 98% to 127%. By taking into account the cumulative impact of growing VC and VC differences, our analyses confirmed high vaccine impact on vaccine-serotype PM case rates and suggest that VC variations cannot explain PM administrative area differences.

Estimation of exposure-attributable fractions from time series: A simulation study.

Burden analysis in public health often involves the estimation of exposure-attributable fractions from observed time series. When the entire population is exposed, the association between the exposure and outcome must be carefully modelled before the attributable fractions can be estimated. This article derives asymptotic convergences for the estimation of attributable fractions for commonly used time series models (ARMAX, Poisson, negative binomial, and Serfling), using for the most part the delta method. For the Poisson regression, the estimation of the attributable fraction is achieved by a Monte Carlo algorithm, taking into account both an estimation and a prediction error. A simulation study compares these estimations in the case of an epidemic exposure and highlights the importance of thorough analysis of the data: When the outcome is generated under an additive model, the additive models are satisfactory, and the multiplicative models are poor, and vice versa. However, the Serfling model performs poorly in all cases. Of note, a misspecification in the form or delay of the association between the exposure and the outcome leads to mediocre estimation of the attributable fraction. An application to the fraction of French outpatient antibiotic use attributable to influenza between 2003 and 2010 illustrates the asymptotic convergences. This study suggests that the Serfling model should be avoided when estimating attributable fractions while the model of choice should be selected after careful investigation of the association between the exposure and outcome.