Effect of early Ambroxol treatment on lung functions in mechanically ventilated preterm newborns who subsequently developed a bronchopulmonary dysplasia (BPD)

AbstractIn a randomized trial in 102 preterm newborns with respiratory distress syndrome (RDS) it has been shown that early Ambroxol treatment (30 mg kg−1over the first 5 days) significantly reduces the incidence of RDS-associated complications [bronchopulmonary dysplasia (BPD), intraventricular haemorrhage, post-natal acquired pneumonia]. The aim of the present analysis was to investigate the effect of Ambroxol treatment on lung function in newborns who developed BPD.Respiratory function testing (RFT) was performed immediately after extubation and at day 28. Tidal volume (VT) and respiratory frequency (f) were measured during tidal breathing using the deadspace free flow-through technique. The lung mechanic parameter VT/maxPeswas determined by measuring the maximal oesophageal pressure changes, maxPes, with a catheter tip pressure transducer.In the placebo group 36/50 infants were extubated within the first 28 days of life and 13/36 (36%) developed BPD. In the Ambroxol group 44/52 were extubated and 9/44 (20%) developed BPD. After extubation, RFT showed (i) no statistically significant difference in the ventilatory parameters of either treatment group, (ii) improved (P<0·05) lung mechanics (VT/maxPes) in Ambroxol group compared to controls (9·4±2·7 ml kPa−1vs. 8·1±2·6 ml kPa−1) and (iii) no statistically significant difference in lung function between infants with and without BPD. At day 28 we found (i) no effect of early Ambroxol treatment on lung functions, (ii) significantly (P<0·05) higher f (58·5±11·7 min−1vs. 49·7±10·1 min−1) and significantly (P<0·01) lower VT(9·6±1·9 ml vs. 12·3±2·7 ml) and VT/maxPes(8·9±2·6 ml kPa−1vs. 12·0±2·9 ml kPa−1) in infants with BPD compared to infants without and (iii) these differences are not influenced by early Ambroxol treatment.If the process of BPD development is induced, early Ambroxol treatment has no influence on impaired lung function at day 28

An improved Plasmodium cynomolgi genome assembly reveals an unexpected methyltransferase gene expansion.

Background: Plasmodium cynomolgi, a non-human primate malaria parasite species, has been an important model parasite since its discovery in 1907. Similarities in the biology of P. cynomolgi to the closely related, but less tractable, human malaria parasite P. vivax make it the model parasite of choice for liver biology and vaccine studies pertinent to P. vivax malaria. Molecular and genome-scale studies of P. cynomolgi have relied on the current reference genome sequence, which remains highly fragmented with 1,649 unassigned scaffolds and little representation of the subtelomeres. Methods: Using long-read sequence data (Pacific Biosciences SMRT technology), we assembled and annotated a new reference genome sequence, PcyM, sourced from an Indian rhesus monkey. We compare the newly assembled genome sequence with those of several other Plasmodium species, including a re-annotated P. coatneyi assembly. Results: The new PcyM genome assembly is of significantly higher quality than the existing reference, comprising only 56 pieces, no gaps and an improved average gene length. Detailed manual curation has ensured a comprehensive annotation of the genome with 6,632 genes, nearly 1,000 more than previously attributed to P. cynomolgi. The new assembly also has an improved representation of the subtelomeric regions, which account for nearly 40% of the sequence. Within the subtelomeres, we identified more than 1300 Plasmodium interspersed repeat (pir) genes, as well as a striking expansion of 36 methyltransferase pseudogenes that originated from a single copy on chromosome 9. Conclusions: The manually curated PcyM reference genome sequence is an important new resource for the malaria research community. The high quality and contiguity of the data have enabled the discovery of a novel expansion of methyltransferase in the subtelomeres, and illustrates the new comparative genomics capabilities that are being unlocked by complete reference genomes

The economic benefit of timely, adequate, and adherence to Parkinson's disease treatment: the Value of Treatment Project 2

Background: Parkinson's disease (PD) is a chronic progressive neurological disorder with a high psychosocial and economic burden. As part of the European Brain Council (EBC)-led Value of Treatment project, this study aimed to capture the economic benefit of timely, adequate, and adherence to PD treatment. Methods: The EBC Value of Treatment Initiative combined different stakeholders to identify unmet needs in the patients’ journey according to Rotterdam methodology. The economic evaluation focused on three major topics identified as major gaps: start of treatment; best treatment for advanced disease; and adherence to treatment. Two separate healthcare systems (Germany and the UK) were chosen. Cost-effectiveness was determined by using decision-analytical modelling approaches. Effectiveness was expressed as quality-adjusted life-years (QALYs) gained and incremental cost-effectiveness ratio (ICER). Results: Treatment intervention in PD was found to be cost-effective regardless of the initial health state of the patient receiving the treatment. Cost savings were between -€1000 and −€5400 with 0.10 QALY gain and -€1800 and -€7600 with 0.10 QALY gain for Germany and the UK, respectively. Treatment remains cost-effective within the National Institute for Health and Care Excellence thresholds. Availability of adequate treatment to more patients was also found to be cost-effective, with an ICER of €15,000–€32,600 across country settings. Achieving the target adherence to treatment would generate cost-savings of €239,000–€576,000 (Germany) and €917,000–€2,980.000 (UK) for every 1,000 patients treated adequately. Conclusions: The analyses confirmed that timely, adequate, and adherence to PD treatment will not only improve care of the patients but is also cost-effective across healthcare systems. Further studies with a distinct identification of gaps in care are necessary to develop better and affordable care

Exhaustive generation of kk-critical H\mathcal H-free graphs

We describe an algorithm for generating all $k$-critical $\mathcal H$-free graphs, based on a method of Ho\`{a}ng et al. Using this algorithm, we prove that there are only finitely many $4$-critical $(P_7,C_k)$-free graphs, for both $k=4$ and $k=5$. We also show that there are only finitely many $4$-critical graphs $(P_8,C_4)$-free graphs. For each case of these cases we also give the complete lists of critical graphs and vertex-critical graphs. These results generalize previous work by Hell and Huang, and yield certifying algorithms for the $3$-colorability problem in the respective classes. Moreover, we prove that for every $t$, the class of 4-critical planar $P_t$-free graphs is finite. We also determine all 27 4-critical planar $(P_7,C_6)$-free graphs. We also prove that every $P_{10}$-free graph of girth at least five is 3-colorable, and determine the smallest 4-chromatic $P_{12}$-free graph of girth five. Moreover, we show that every $P_{13}$-free graph of girth at least six and every $P_{16}$-free graph of girth at least seven is 3-colorable. This strengthens results of Golovach et al.Comment: 17 pages, improved girth results. arXiv admin note: text overlap with arXiv:1504.0697

Mining State-Based Models from Proof Corpora

Interactive theorem provers have been used extensively to reason about various software/hardware systems and mathematical theorems. The key challenge when using an interactive prover is finding a suitable sequence of proof steps that will lead to a successful proof requires a significant amount of human intervention. This paper presents an automated technique that takes as input examples of successful proofs and infers an Extended Finite State Machine as output. This can in turn be used to generate proofs of new conjectures. Our preliminary experiments show that the inferred models are generally accurate (contain few false-positive sequences) and that representing existing proofs in such a way can be very useful when guiding new ones.Comment: To Appear at Conferences on Intelligent Computer Mathematics 201

Fragmentation transitions in multi-state voter models

Adaptive models of opinion formation among humans can display a fragmentation transition, where a social network breaks into disconnected components. Here, we investigate this transition in a class of models with arbitrary number of opinions. In contrast to previous work we do not assume that opinions are equidistant or arranged on a one-dimensional conceptual axis. Our investigation reveals detailed analytical results on fragmentations in a three-opinion model, which are confirmed by agent-based simulations. Furthermore, we show that in certain models the number of opinions can be reduced without affecting the fragmentation points.Comment: 11 pages, 8 figure

A new testudinoid turtle from the middle to late Eocene of Vietnam

Testudinoidea is a major clade of turtles that has colonized different ecological environments across the globe throughout the Tertiary. Aquatic testudinoids have a particularly rich fossil record in the Tertiary of the northern hemisphere, but little is known about the evolutionary history of the group, as the phylogenetic relationships of most fossils have not been established with confidence, in part due to high levels of homoplasy and polymorphism.Methods: We here focus on describing a sample of 30 testudinoid shells, belonging to a single population that was collected from lake sediments from the middle to late Eocene (35–39 Ma) Na Duong Formation in Vietnam. The phylogenetic placement of this new material is investigated by integrating it and 11 other species of putative geoemydids from the Eocene and Oligocene to a recently published matrix of geoemydid turtles, that embraces the use of polymorphic characters, and then running a total-evidence analysis.Results: The new material is highly polymorphic, but can be inferred with confidence to be a new taxon, Banhxeochelys trani gen. et sp. nov. It shares morphological similarities with other southeastern Asian testudinoids, Isometremys lacuna and Guangdongemys pingi, but is placed phylogenetically at the base of Pan-Testuguria when fossils are included in the analysis, or as a stem geoemydid when other fossils are deactivated from the matrix. The vast majority of other putative fossil geoemydids are placed at the base of Pan-Testuguria as well.Discussion: The phylogenetic placement of fossil testudinoids used in the analysis is discussed individually and each species compared to Banhxeochelys trani gen. et sp. nov. The high levels of polymorphism observed in the new taxon is discussed in terms of ontogenetic and random variability. This is the first time that a large sample of fossil testudinoids has its morphological variation described in detail

Treatment of invasive fungal infections in clinical practice: a multi-centre survey on customary dosing, treatment indications, efficacy and safety of voriconazole

Invasive fungal infections are frequent and often deadly complications in patients with malignant hematological diseases. Voriconazole is a third generation triazole antifungal with broad activity against most clinically relevant fungal pathogens. Clinical practice often deviates from insights gained from controlled randomized trials. We conducted a multi-centre survey to evaluate efficacy, safety, treatment indications and dosing of voriconazole outside clinical trials. Patients receiving voriconazole were documented via electronic data capturing. An analysis was conducted after submission of 100 episodes from September 2004 to November 2005. Voriconazole was administered for suspected or proven invasive fungal infection (IFI) (57%), as empirical treatment in patients with fever of unknown origin (21%) and secondary (19%) as well as primary (3%) prophylaxis of IFI. Investigators’ assessment of fungal infection often diverted from EORTC/MSG 2002 criteria. A favorable response was reported in 61.4% for suspected or proven IFI and 52.4% for empirical treatment. Mortality was 15%, 26.7% of which was attributable to IFI. Breakthrough fungal infections occurred in four (21.1%) patients with voriconazole as secondary prophylaxis. Toxicity and adverse events comprised elevated liver enzymes and visual disturbances. Although indications frequently deviated from clinical evidence and legal approval, voriconazole showed efficacy and safety, comparable to major controlled clinical trials. Data from this survey demonstrate the difficulty of putting drugs to their approved use in IFI