Combination Antifungal Therapy for Invasive Mold Infections Among Pediatric Patients with Hematological Malignancies : Data from A Real-Life Case-Series

Background: Invasive mold infections in children with hematological malignancies are associated with high mortality rates. The use of combination antifungal therapy in cases with a severe clinical course is increasing, although information on the efficacy and safety of this approach is limited. Methods: We present a case series of 13 children affected by hemato-oncological disorders who received combination antifungal therapy for invasive mold infections at our center (Pediatric Hematology, San Gerardo Hospital, Monza, Italy) from 2011 to 2016, with the aim of describing their clinical characteristics, types of infections, treatment regimens, clinical outcomes, and treatment safety. Medical records were retrospectively reviewed in order to describe patients' characteristics. Results: Combination antifungal therapy included liposomal amphotericin associated with caspofungin (5/13, 38.4%), voriconazole (5/13, 38.4%), or posaconazole (3/13, 23.1%). The 12-week treatment response rate was 69.2% (6/13 patients showed complete response, 3/13 partial response). The crude mortality was 30.7% (4/13): half was related to invasive mold infections (2/13, 15.38%) and half to disease progression (2/13, 15.38%). Overall, treatment was well tolerated, and we did not observe any permanent discontinuation of antifungals due to related side effects. Conclusions: In our experience, combination antifungal therapy seems to be a safe option in immunocompromised children with invasive mold infections. Well-designed studies are needed to confirm the safety of this approach and to better understand its efficacy in the pediatric setting

The DESiGN trial (DEtection of Small for Gestational age Neonate), evaluating the effect of the Growth Assessment Protocol (GAP): study protocol for a randomised controlled trial.

BACKGROUND: Stillbirth rates in the United Kingdom (UK) are amongst the highest of all developed nations. The association between small-for-gestational-age (SGA) foetuses and stillbirth is well established, and observational studies suggest that improved antenatal detection of SGA babies may halve the stillbirth rate. The Growth Assessment Protocol (GAP) describes a complex intervention that includes risk assessment for SGA and screening using customised fundal-height growth charts. Increased detection of SGA from the use of GAP has been implicated in the reduction of stillbirth rates by 22%, in observational studies of UK regions where GAP uptake was high. This study will be the first randomised controlled trial examining the clinical efficacy, health economics and implementation of the GAP programme in the antenatal detection of SGA. METHODS/DESIGN: In this randomised controlled trial, clusters comprising a maternity unit (or National Health Service Trust) were randomised to either implementation of the GAP programme, or standard care. The primary outcome is the rate of antenatal ultrasound detection of SGA in infants found to be SGA at birth by both population and customised standards, as this is recognised as being the group with highest risk for perinatal morbidity and mortality. Secondary outcomes include antenatal detection of SGA by population centiles, antenatal detection of SGA by customised centiles, short-term maternal and neonatal outcomes, resource use and economic consequences, and a process evaluation of GAP implementation. Qualitative interviews will be performed to assess facilitators and barriers to implementation of GAP. DISCUSSION: This study will be the first to provide data and outcomes from a randomised controlled trial investigating the potential difference between the GAP programme compared to standard care for antenatal ultrasound detection of SGA infants. Accurate information on the performance and service provision requirements of the GAP protocol has the potential to inform national policy decisions on methods to reduce the rate of stillbirth. TRIAL REGISTRATION: Primary registry and trial identifying number: ISRCTN 67698474 . Registered on 2 November 2016

Validation of the INCREMENT-SOT-CPE score in a large cohort of liver transplant recipients with carbapenem-resistant Enterobacterales infection

Background: Management of infections due to carbapenemase-resistant Enterobacterales (CRE) in solid organ transplant (SOT) recipients remains a difficult challenge. The INCREMENT-SOT-CPE score has been specifically developed from SOT recipients to stratify mortality risk, but an external validation is lacking.Methods: Multicenter retrospective cohort study of liver transplant (LT) recipients colonized with CRE infection who developed infection after transplant over 7-year period. Primary endpoint was all-cause 30-day mortality from infection onset. A comparison between INCREMENT-SOT-CPE and other selected scores was performed. A two-level mixed effects logistic regression model with random effects for the center was fitted. Performance characteristics at optimal cut-point were calculated. Multivariable Cox regression analysis of risk factors for all-cause 30-day mortality was carried out.Results: Overall, 250 CRE carriers developed infection after LT and were analyzed. The median age was 55 years (interquartile range [IQR]: 46-62) and 157 were males (62.8%). All-cause 30-day mortality was 35.6%. A sequential organ failure assessment (SOFA) score >= 11 showed a sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 69.7%, 76.4%, 62.0%, 82.0%, and 74.0%, respectively. An INCREMENT-SOT-CPE >= 11 reported a sensitivity, specificity, PPV, NPV, and accuracy of 73.0%, 62.1%, 51.6%, 80.6% and 66.0%, respectively. At multivariable analysis acute renal failure, prolonged mechanical ventilation, INCREMENT-SOT-CPE score >= 11 and SOFA score >= 11 were independently associated with all-cause 30-day mortality, while a tigecycline-based targeted regimen was found to be protective.Conclusions: Both INCREMENT-SOT-CPE >= 11 and SOFA >= 11 were identified as strong predictors of all-cause 30-day mortality in a large cohort of CRE carriers developing infection after LT

Sequencing, de novo annotation and analysis of the first Anguilla anguilla transcriptome: EeelBase opens new perspectives for the study of the critically endangered european eel

Background: Once highly abundant, the European eel (Anguilla anguilla L.; Anguillidae; Teleostei) is considered to be critically endangered and on the verge of extinction, as the stock has declined by 90-99% since the 1980s. Yet, the species is poorly characterized at molecular level with little sequence information available in public databases.\ud \ud Results: The first European eel transcriptome was obtained by 454 FLX Titanium sequencing of a normalized cDNA library, produced from a pool of 18 glass eels (juveniles) from the French Atlantic coast and two sites in the Mediterranean coast. Over 310,000 reads were assembled in a total of 19,631 transcribed contigs, with an average length of 531 nucleotides. Overall 36% of the contigs were annotated to known protein/nucleotide sequences and 35 putative miRNA identified.\ud \ud Conclusions: This study represents the first transcriptome analysis for a critically endangered species. EeelBase, a dedicated database of annotated transcriptome sequences of the European eel is freely available at http://compgen.bio.unipd.it/eeelbase. Considering the multiple factors potentially involved in the decline of the European eel, including anthropogenic factors such as pollution and human-introduced diseases, our results will provide a rich source of data to discover and identify new genes, characterize gene expression, as well as for identification of genetic markers scattered across the genome to be used in various applications

Antenatal detection of large-for-gestational-age fetuses following implementation of the Growth Assessment Protocol: secondary analysis of a randomised control trial.

OBJECTIVE: To determine whether the Growth Assessment Protocol (GAP) affects the antenatal detection of large for gestational age (LGA) or maternal and perinatal outcomes amongst LGA babies. DESIGN: Secondary analysis of a pragmatic open randomised cluster control trial comparing the GAP with standard care. SETTING: Eleven UK maternity units. POPULATION: Pregnant women and their LGA babies born at ≥36+0  weeks of gestation. METHODS: Clusters were randomly allocated to GAP implementation or standard care. Data were collected from electronic patient records. Trial arms were compared using summary statistics, with unadjusted and adjusted (two-stage cluster summary approach) differences. MAIN OUTCOME MEASURES: Rate of detection of LGA (estimated fetal weight on ultrasound scan above the 90th centile after 34+0  weeks of gestation, defined by either population or customised growth charts), maternal and perinatal outcomes (e.g. mode of birth, postpartum haemorrhage, severe perineal tears, birthweight and gestational age, neonatal unit admission, perinatal mortality, and neonatal morbidity and mortality). RESULTS: A total of 506 LGA babies were exposed to GAP and 618 babies received standard care. There were no significant differences in the rate of LGA detection (GAP 38.0% vs standard care 48.0%; adjusted effect size -4.9%; 95% CI -20.5, 10.7; p = 0.54), nor in any of the maternal or perinatal outcomes. CONCLUSIONS: The use of GAP did not change the rate of antenatal ultrasound detection of LGA when compared with standard care

Exploring the Switchgrass Transcriptome Using Second-Generation Sequencing Technology

Background: Switchgrass (Panicum virgatum L.) is a C4 perennial grass and widely popular as an important bioenergy crop. To accelerate the pace of developing high yielding switchgrass cultivars adapted to diverse environmental niches, the generation of genomic resources for this plant is necessary. The large genome size and polyploid nature of switchgrass makes whole genome sequencing a daunting task even with current technologies. Exploring the transcriptional landscape using next generation sequencing technologies provides a viable alternative to whole genome sequencing in switchgrass. Principal Findings: Switchgrass cDNA libraries from germinating seedlings, emerging tillers, flowers, and dormant seeds were sequenced using Roche 454 GS-FLX Titanium technology, generating 980,000 reads with an average read length of 367 bp. De novo assembly generated 243,600 contigs with an average length of 535 bp. Using the foxtail millet genome as a reference greatly improved the assembly and annotation of switchgrass ESTs. Comparative analysis of the 454-derived switchgrass EST reads with other sequenced monocots including Brachypodium, sorghum, rice and maize indicated a 70– 80 % overlap. RPKM analysis demonstrated unique transcriptional signatures of the four tissues analyzed in this study. More than 24,000 ESTs were identified in the dormant seed library. In silico analysis indicated that there are more than 2000 EST-SSRs in this collection. Expression of several orphan ESTs was confirmed by RT-PCR. Significance: We estimate that about 90 % of the switchgrass gene space has been covered in this analysis. This study nearl

Effect of the Growth Assessment Protocol on the DEtection of Small for GestatioNal age fetus: process evaluation from the DESiGN cluster randomised trial.

BACKGROUND: Reducing the rate of stillbirth is an international priority. At least half of babies stillborn in high-income countries are small for gestational-age (SGA). The Growth Assessment Protocol (GAP), a complex antenatal intervention that aims to increase the rate of antenatal detection of SGA, was evaluated in the DESiGN type 2 hybrid effectiveness-implementation cluster randomised trial (n = 13 clusters). In this paper, we present the trial process evaluation. METHODS: A mixed-methods process evaluation was conducted. Clinical leads and frontline healthcare professionals were interviewed to inform understanding of context (implementing and standard care sites) and GAP implementation (implementing sites). Thematic analysis of interview text used the context and implementation of complex interventions framework to understand acceptability, feasibility, and the impact of context. A review of implementing cluster clinical guidelines, training and maternity records was conducted to assess fidelity, dose and reach. RESULTS: Interviews were conducted with 28 clinical leads and 27 frontline healthcare professionals across 11 sites. Staff at implementing sites generally found GAP to be acceptable but raised issues of feasibility, caused by conflicting demands on resource, and variable beliefs among clinical leaders regarding the intervention value. GAP was implemented with variable fidelity (concordance of local guidelines to GAP was high at two sites, moderate at two and low at one site), all sites achieved the target to train > 75% staff using face-to-face methods, but only one site trained > 75% staff using e-learning methods; a median of 84% (range 78-87%) of women were correctly risk stratified at the five implementing sites. Most sites achieved high scores for reach (median 94%, range 62-98% of women had a customised growth chart), but generally, low scores for dose (median 31%, range 8-53% of low-risk women and median 5%, range 0-17% of high-risk women) were monitored for SGA as recommended. CONCLUSIONS: Implementation of GAP was generally acceptable to staff but with issues of feasibility that are likely to have contributed to variation in implementation strength. Leadership and resourcing are fundamental to effective implementation of clinical service changes, even when such changes are well aligned to policy mandated service-change priorities. TRIAL REGISTRATION: Primary registry and trial identifying number: ISRCTN 67698474. Registered 02/11/16. https://doi.org/10.1186/ISRCTN67698474