Detection of clusters of a rare disease over a large territory: performance of cluster detection methods

International audienceBackgroundFor many years, the detection of clusters has been of great public health interest. Several detection methods have been developed, the most famous of which is the circular scan method. The present study, which was conducted in the context of a rare disease distributed over a large territory (7675 cases registered over 17 years and located in 1895 units), aimed to evaluate the performance of several of the methods in realistic hot-spot cluster situations.MethodsAll the methods considered aim to identify the most likely cluster area, i.e. the zone that maximizes the likelihood ratio function, among a set of cluster candidates. The circular and elliptic scan methods were developed to detect regularly shaped clusters. Four other methods that focus on irregularly shaped clusters were also considered (the flexible scan method, the genetic algorithm method, and the double connected and maximum linkage spatial scan methods). The power of the methods was evaluated via Monte Carlo simulations under 27 alternative scenarios that corresponded to three cluster population sizes (20, 45 and 115 expected cases), three cluster shapes (linear, U-shaped and compact) and three relative risk values (1.5, 2.0 and 3.0).ResultsThree situations emerged from this power study. All the methods failed to detect the smallest clusters with a relative risk lower than 3.0. The power to detect the largest cluster with relative risk of 1.5 was markedly better for all methods, but, at most, half of the true cluster was captured. For other clusters, either large or with the highest relative risk, the standard elliptic scan method appeared to be the best method to detect linear clusters, while the flexible scan method localized the U-shaped clusters more precisely than other methods. Large compact clusters were detected well by all methods, with better results for the circular and elliptic scan methods.ConclusionsThe elliptic scan method and flexible scan method seemed the most able to detect clusters of a rare disease in a large territory. However, the probability of detecting small clusters with relative risk lower than 3.0 remained low with all the methods tested

Residential exposure to solar ultraviolet radiation and incidence of childhood hematological malignancies in France

Few studies have investigated the relationship between solar ultraviolet radiation (UV) and childhood hematological malignancies (CHM). This study addresses the associations between residential UV exposure at diagnosis and the incidence of types and subtypes of CHM, by age and gender, in France, over a long period, on the fine scale of the 36,326 Communes that constitute mainland France. The 9,082 cases of acute leukemia and 3,563 cases of lymphoma diagnosed before the age of 15 years from 1990 to 2009 were provided by the French National Registry of Childhood Hematological Malignancies. The incidence of CHM was calculated by Commune, year, age and gender and expressed as the standardized incidence ratio (SIR). UV data from 1988 to 2007 were extracted from the EUROSUN database. The annual daily average UV exposure of the children ranged from 85.5 to 137.8 J/cm2. For each additional 25 J/cm2, there was a significant increase in precursor B-cell acute lymphoblastic leukemia (PBC-ALL) in children aged less than 5 years (SIR 1.18; 95 % CI 1.10–1.27). Further analysis of PBC-ALL in the young children suggested a better fit of models with a threshold, with the risk increasing above 100 J/cm2, for which the SIR was 1.24 (95 % CI 1.14–1.36) for a 25 J/cm2 increase. The results remained stable in analyses stratifying by deprivation index or degree of urbanization of the Communes. The study suggests that higher residential UV exposure may be positively associated with a higher incidence of PBC-ALL in early childhood

APOBEC3A Is a Specific Inhibitor of the Early Phases of HIV-1 Infection in Myeloid Cells

Myeloid cells play numerous roles in HIV-1 pathogenesis serving as a vehicle for viral spread and as a viral reservoir. Yet, cells of this lineage generally resist HIV-1 infection when compared to cells of other lineages, a phenomenon particularly acute during the early phases of infection. Here, we explore the role of APOBEC3A on these steps. APOBEC3A is a member of the APOBEC3 family that is highly expressed in myeloid cells, but so far lacks a known antiviral effect against retroviruses. Using ectopic expression of APOBEC3A in established cell lines and specific silencing in primary macrophages and dendritic cells, we demonstrate that the pool of APOBEC3A in target cells inhibits the early phases of HIV-1 infection and the spread of replication-competent R5-tropic HIV-1, specifically in cells of myeloid origins. In these cells, APOBEC3A affects the amount of vDNA synthesized over the course of infection. The susceptibility to the antiviral effect of APOBEC3A is conserved among primate lentiviruses, although the viral protein Vpx coded by members of the SIVSM/HIV-2 lineage provides partial protection from APOBEC3A during infection. Our results indicate that APOBEC3A is a previously unrecognized antiviral factor that targets primate lentiviruses specifically in myeloid cells and that acts during the early phases of infection directly in target cells. The findings presented here open up new venues on the role of APOBEC3A during HIV infection and pathogenesis, on the role of the cellular context in the regulation of the antiviral activities of members of the APOBEC3 family and more generally on the natural functions of APOBEC3A

Characterization of a cinnamoyl-CoA reductase 1 (CCR1) mutant in maize: effects on lignification, fibre development, and global gene expression

Cinnamoyl-CoA reductase (CCR), which catalyses the first committed step of the lignin-specific branch of monolignol biosynthesis, has been extensively characterized in dicot species, but few data are available in monocots. By screening a Mu insertional mutant collection in maize, a mutant in the CCR1 gene was isolated named Zmccr1–. In this mutant, CCR1 gene expression is reduced to 31% of the residual wild-type level. Zmccr1– exhibited enhanced digestibility without compromising plant growth and development. Lignin analysis revealed a slight decrease in lignin content and significant changes in lignin structure. p-Hydroxyphenyl units were strongly decreased and the syringyl/guaiacyl ratio was slightly increased. At the cellular level, alterations in lignin deposition were mainly observed in the walls of the sclerenchymatic fibre cells surrounding the vascular bundles. These cell walls showed little to no staining with phloroglucinol. These histochemical changes were accompanied by an increase in sclerenchyma surface area and an alteration in cell shape. In keeping with this cell type-specific phenotype, transcriptomics performed at an early stage of plant development revealed the down-regulation of genes specifically associated with fibre wall formation. To the present authors’ knowledge, this is the first functional characterization of CCR1 in a grass species

Limited usefulness of neurocognitive functioning indices as predictive markers for treatment response to methylphenidate or neurofeedback@home in children and adolescents with ADHD

IntroductionEarlier studies exploring the value of executive functioning (EF) indices for assessing treatment effectiveness and predicting treatment response in attention-deficit/hyperactivity disorder (ADHD) mainly focused on pharmacological treatment options and revealed rather heterogeneous results. Envisioning the long-term goal of personalized treatment selection and intervention planning, this study comparing methylphenidate treatment (MPH) and a home-based neurofeedback intervention (NF@Home) aimed to expand previous findings by assessing objective as well as subjectively reported EF indices and by analyzing their value as treatment and predictive markers.MethodsChildren and adolescents (n = 146 in the per protocol sample) aged 7–13 years with a formal diagnosis of an inattentive or combined presentation of ADHD were examined. We explored the EF performance profile using the Conners Continuous Performance Task (CPT) and the BRIEF self-report questionnaire within our prospective, multicenter, randomized, reference drug-controlled NEWROFEED study with sites in five European countries (France, Spain, Switzerland, Germany, and Belgium). As primary outcome for treatment response, the clinician-rated ADHD Rating Scale-IV was used. Patients participating in this non-inferiority trial were randomized to either NF@home (34–40 sessions of TBR or SMR NF depending on the pre-assessed individual alpha peak frequency) or MPH treatment (ratio: 3:2). Within a mixed-effects model framework, analyses of change were calculated to explore the predictive value of neurocognitive indices for ADHD symptom-related treatment response.ResultsFor a variety of neurocognitive indices, we found a significant pre-post change during treatment, mainly in the MPH group. However, the results of the current study reveal a rather limited prognostic value of neurocognitive indices for treatment response to either NF@Home or MPH treatment. Some significant effects emerged for parent-ratings only.DiscussionCurrent findings indicate a potential value of self-report (BRIEF global score) and some objectively measured neurocognitive indices (CPT commission errors and hit reaction time variability) as treatment markers (of change) for MPH. However, we found a rather limited prognostic value with regard to predicting treatment response not (yet) allowing recommendation for clinical use. Baseline symptom severity was revealed as the most relevant predictor, replicating robust findings from previous studies

Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin antitumor effects

Cisplatin is a potent chemotherapeutic drug that is widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, in particular nephrotoxicity and chemotherapy-induced peripheral neuropathy. Thus, there is an urgent medical need to identify novel strategies that limit cisplatin-induced toxicity. In the present study, we show that the FDA-approved adenosine A2A receptor antagonist istradefylline (KW6002) protected from cisplatin-induced nephrotoxicity and neuropathic pain in mice with or without tumors. Moreover, we also demonstrate that the antitumoral properties of cisplatin were not altered by istradefylline in tumor-bearing mice and could even be potentiated. Altogether, our results support the use of istradefylline as a valuable preventive approach for the clinical management of patients undergoing cisplatin treatment

Seasonal variations in childhood leukaemia incidence in France, 1990–2014

International audienceBackground Several studies have addressed the potential seasonality of childhood acute leukaemia (AL) without conclusive results. Using data from the National Registry of Childhood Cancers over 1990-2014 in mainland France, we investigated the seasonal variations in childhood AL taken together, and lymphoblastic (ALL) and myeloid (AML) leukaemia separately. Methods Assuming constant variations over 1990-2014, we used a Poisson regression model to evaluate variations in standardized incidence ratios (SIRs) by month of birth or diagnosis. A scan method for temporal cluster detection was used to identify windows of several consecutive months with high or low SIR. The yearly reproducibility of the observed monthly variations was then evaluated. Results We included 11,528 AL, of which 9,493 ALL and 1,843 AML. No seasonal variation was detected for ALL. With a clear seasonal pattern, differences in AML incidence rates were evidenced between January-April and May-December birth periods (SIR=0.85 95% CI 0.77-0.94 and SIR=1.07 95% CI 1.01-1.14, respectively). AML incidence variations by month of diagnosis were less clear-cut. Conclusion Based on a large number of cases from a high-quality registry, we did not evidence any seasonality in ALL incidence rates but evidenced seasonal variations in AML incidence rates by month of birth

Agricultural crop density in the municipalities of France and incidence of childhood leukemia: An ecological study.

BACKGROUND Pesticide exposure is suspected to play a role in the etiology of childhood leukemia (AL). Various sources of exposure have been explored, but few studies have investigated the risk of childhood AL in relation to residential exposure to agricultural pesticides. Since around 50% of France is agricultural land, with marked pesticide use, France is a suitable location to investigate for an association. We aimed to analyze the association between the agricultural crop density in the municipalities of France and the incidence of childhood AL between 1990 and 2014. METHODS 11,487 cases of AL diagnosed in children aged 0-14 years were registered by the French National Registry of Childhood Hematological Malignancies over 1990-2014. National agricultural census data for 1990, 2000 and 2010 were used to estimate the densities of the most common crops in France. The incidence of AL was estimated in the 35,512 municipalities, by age and gender, and 3 observation periods, and expressed as the standardized incidence ratio (SIR). RESULTS We observed a moderate log-linear association between viticulture density and the incidence of AL, with a 3% increase in SIR for a 10% increase in viticulture density (SIRR = 1.03; 95%CI [1.00-1.06]). The association remained for lymphoblastic AL but not for myeloid AL. The association was stable after stratification by geographic area, age and period, and after adjustment on UV radiation and a French deprivation index. No consistent association was observed for other crop types. DISCUSSION This nationwide study shows a moderate increase in incidence of childhood AL in municipalities where viticulture is common. Future individual studies are needed to know whether this observation is confirmed and related to particular use of pesticides

Use of ESR and HPLC to follow the anaerobic reaction catalysed by lipoxygenases

The measurement of the 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) consumption by using ESR allows to follow the anaerobic reaction between linoleic acid (LH) and its 13-hydroperoxide (LOOH) catalysed by lipoxygenase. During this reaction, two types of radicals are initially obtained, alkyl (L ) and alkoxyl (LO ) radicals which formed two types of adducts (LT and OLT) with TEMPOL as characterised by HPLC. The stoichiometry of the adduct formation is two mole of TEMPOL consumed for one mole of LH and one mole of LOOH. Using ESR, the kinetic parameters and the mechanism of the anaerobic reaction have been determined at pH 6.5 for three different lipoxygenases, soybean, horse bean and wheat and compared to the values obtained at pH 9 for soybean lipoxygenase. Wheat lipoxygenase is very weakly active compared to the other enzymes. An uncompetitive inhibition of the anaerobic reaction catalysed by soybean and horse bean lipoxygenases was observed with 2,6-di-tert-butyl-4-methylphenol (BHT)