Disentangling the effects of different human disturbances on multifaceted biodiversity indices in freshwater fish.

Evaluating the effects of anthropogenic pressures on several biodiversity metrics can inform the management and monitoring of biodiversity loss. However, the type of disturbances can lead to different responses in different metrics. In this study, we aimed at disentangling the effects of different types of anthropogenic disturbances on freshwater fish communities. We calculated diversity indices for 1109 stream fish communities across France by computing richness and evenness components for ecological, morphological, and phylogenetic diversity, and used null models to estimate standardized effect sizes. We used generalized linear mixed models to assess the relative effects of environmental and anthropogenic drivers in driving those diversity indices. Our results demonstrated that all diversity indices exhibited significant responses to both climatic conditions and anthropogenic disturbances. While we observed a decrease of ecological and phylogenetic richness with the intensity of disturbance, a weak increase in morphological richness and evenness was apparent. Overall, our results demonstrated the importance of disentangling various types of disturbances when assessing human-induced ecological impacts and highlighted that different facets of diversity are not impacted identically by anthropogenic disturbances in stream fish communities. This calls for further work seeking to integrate biodiversity responses to human disturbances into a multifaceted framework, and could have beneficial implications when planning conservation action in freshwater ecosystems.

Decision-tree derivation and external validation of a new clinical decision rule (DISCERN-FN) to predict the risk of severe infection during febrile neutropenia in children treated for cancer.

BACKGROUND: In 2017, international guidelines proposed new management of febrile neutropenia in children with cancer, adapted to the risk of severe infection by clinical decision rules (CDRs). Until now, none of the proposed CDRs has performed well enough in high-income countries for use in clinical practice. Our study aimed to build and validate a new CDR (DISCERN-FN) to predict the risk of severe infection in children with febrile neutropenia. METHODS: We did two prospective studies. First, a prospective derivation study included all episodes of febrile neutropenia in children (aged <18 years) with a cancer diagnosis and receiving treatment for it who were admitted for an episode of febrile neutropenia, excluding patients already treated with antibiotics for this episode, febrile neutropenia not induced by chemotherapy, those receiving palliative care, and those with a stem cell allograft for less than 1 year, from April 1, 2007, to Dec 31, 2011 from two paediatric cancer centres in France. We collected the children's medical history, and clinical and laboratory data, and analysed their associations with severe infection. Sipina software was used to derive the CDR as a decision tree. Second, a prospective, national, external validation study was done in 23 centres from Jan 1, 2012, to May 31, 2016. The primary outcome was severe infection, defined by bacteraemia, a positive bacterial culture from a usually sterile site, a local infection with a high potential for extension, or an invasive fungal infection. The CDR was applied a posteriori to all episodes to evaluate its sensitivity, specificity, and negative likelihood ratio. FINDINGS: The derivation set included 539 febrile neutropenia episodes (270 episodes in patients with blood cancer [median age 7·5 years, IQR 3·7-11·2; 158 (59 %) boys and 112 (41%) girls] and 269 in patients with solid tumours [median age 6·6 years, IQR 2·9-14·2; 140 (52 %) boys and 129 (48%) girls]). Significant variables introduced into the decision tree were cancer type (solid tumour vs blood cancer), age, high-risk chemotherapy, level of fever, C-reactive protein concentration (at 24-48 h after admission), and leucocyte and platelet counts and procalcitonin (at admission and at 24-48 h after admission). For the derivation set, the CDR sensitivity was 98% (95% CI 93-100), its specificity 56% (51-61), and the negative likelihood ratio 0·04 (0·01-0·15). 1806 febrile neutropenia episodes were analysed in the validation set (mean age 8·1 years [SD 4·8], 1014 (56%) boys and 792 (44%) girls), of which 332 (18%, 95% CI 17-20) were linked with severe infection. For the validation set, the CDR had a sensitivity of 95% (95% CI 91-97), a specificity of 38% (36-41), and a negative likelihood ratio of 0·13 (0·08-0·21). Our CDR reduced the risk of severe infection to a post-test probability of 0·8% (95% CI 0·2-2·9) in the derivation set and 2·4% (1·5-3·9) in the validation set. The validation study is registered at ClinicalTrials.gov, NCT03434795. INTERPRETATION: The use of our CDR substantially reduced the risk of severe infection after testing in both the derivation and validation groups, which suggests that this CDR would improve clinical practice enough to be introduced in appropriate settings. FUNDING: Ligue Nationale Contre le Cancer.

Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study.

PURPOSE: Off-label use of vemurafenib (VMF) to treat BRAFV600E mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated. PATIENTS AND METHODS: Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events [version 4.3]) and therapeutic responses according to Disease Activity Score. RESULTS: LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 (P < .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood BRAFV600E allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment; P < .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the BRAFV600E clone. CONCLUSION: VMF seemed safe and effective in children with refractory BRAFV600E-positive LCH. Additional studies are needed to find effective maintenance therapy approaches.

Determinants of neonatal weight loss in term-infants: specific association with pre-pregnancy maternal body mass index and infant feeding mode.

OBJECTIVE: We aimed to study the determinants of neonatal weight loss measured on the third day of life in term-infants. DESIGN: The EDEN mother-child cohort is a prospective study that recruited 2002 pregnant women before 24 weeks of gestation in two French university hospitals. Neonates were weighed every day until discharge that occurred on average 4.5 days after birth. Altogether, 1557 healthy term neonates with data on weight at day 3 and feeding mode available were included. The outcome variable was weight loss at day 3 (D3WL), expressed as a percentage of birth weight lost in the first 3 days of life. Our main explanatory variables were maternal pre-pregnancy body mass index (BMI), gestational weight gain, gestational diabetes, birth weight, gestational age and feeding mode. RESULTS: Factors associated with greater D3WL, whatever the feeding mode, were: higher birth weight, gestational diabetes and caesarean section; higher gestational age was associated with a reduced D3WL. The association between maternal pre-pregnancy BMI and D3WL differed by feeding mode (interaction p value=0.0002). In breastfed babies, mean D3WL ranged from 4.9% for neonates of underweight mothers to 5.8% for neonates of obese mothers (p trend=0.0005). In formula-fed babies, D3WL was highest for neonates of underweight mothers (4.1%) and lowest for those of obese mothers (2.6%) (p trend=0.01). CONCLUSIONS: The lower D3WL in formula-fed neonates, especially in neonates of obese mothers, suggests a relative overfeeding in the early days compared with breastfed neonates, which may potentially have consequences on later health. Overweight and obese mothers may need extra support to prevent early breastfeeding discontinuation.