Osteogenesis imperfecta: from diagnosis and multidisciplinary treatment to future perspectives.

Osteogenesis imperfecta is an inherited connective tissue disorder with wide phenotypic and molecular heterogeneity. A common issue associated with the molecular abnormality is a disturbance in bone matrix synthesis and homeostasis inducing bone fragility. In very early life, this can lead to multiple fractures and progressive bone deformities, including long bone bowing and scoliosis. Multidisciplinary management improves quality of life for patients with osteogenesis imperfecta. It consists of physical therapy, medical treatment and orthopaedic surgery as necessary. Medical treatment consists of bone-remodelling drug therapy. Bisphosphonates are widely used in the treatment of moderate to severe osteogenesis imperfecta, from infancy to adulthood. Other more recent drug therapies include teriparatide and denosumab. All these therapies target the symptoms and have effects on the mechanical properties of bone due to modification of bone remodelling, therefore influencing skeletal outcome and orthopaedic surgery. Innovative therapies, such as progenitor and mesenchymal stem cell transplantation, targeting the specific altered pathway rather than the symptoms, are in the process of development

Satisfiability Checking for Mission-Time LTL

Mission-time LTL (MLTL) is a bounded variant of MTL over naturals designed to generically specify requirements for mission-based system operation common to aircraft, spacecraft, vehicles, and robots. Despite the utility of MLTL as a specification logic, major gaps remain in analyzing MLTL, e.g., for specification debugging or model checking, centering on the absence of any complete MLTL satisfiability checker. We prove that the MLTL satisfiability checking problem is NEXPTIME-complete and that satisfiability checking MLTL0 , the variant of MLTL where all intervals start at 0, is PSPACE-complete. We introduce translations for MLTL-to-LTL, MLTL-to-LTLf , MLTL-to-SMV, and MLTL-to-SMT, creating four options for MLTL satisfiability checking. Our extensive experimental evaluation shows that the MLTL-to-SMT transition with the Z3 SMT solver offers the most scalable performance

Office-Based Preventive Dental Program and Statewide Trends in Dental Caries

To evaluate the impact of a North Carolina Medicaid preventive dentistry program in primary care medical offices (Into the Mouths of Babes Program [IMBP]) on decayed, missing, and filled teeth (dmft) of kindergarten students statewide and in schools with a large proportion of students from low-income families

Specification: The Biggest Bottleneck in Formal Methods and Autonomy

Advancement of AI-enhanced control in autonomous systems stands on the shoulders of formal methods, which make possible the rigorous safety analysis autonomous systems require. An aircraft cannot operate autonomously unless it has design-time reasoning to ensure correct operation of the autopilot and runtime reasoning to ensure system health management, or the ability to detect and respond to off-nominal situations. Formal methods are highly dependent on the specifications over which they reason; there is no escaping the “garbage in, garbage out” reality. Specification is difficult, unglamorous, and arguably the biggest bottleneck facing verification and validation of aerospace, and other, autonomous systems. This VSTTE invited talk and paper examines the outlook for the practice of formal specification, and highlights the on-going challenges of specification, from design-time to runtime system health management. We exemplify these challenges for specifications in Linear Temporal Logic (LTL) though the focus is not limited to that specification language. We pose challenge questions for specification that will shape both the future of formal methods, and our ability to more automatically verify and validate autonomous systems of greater variety and scale. We call for further research into LTL Genesis

Mightyl: A compositional translation from mitl to timed automata

Metric Interval Temporal Logic (MITL) was first proposed in the early 1990s as a specification formalism for real-time systems. Apart from its appealing intuitive syntax, there are also theoretical evidences that make MITL a prime real-time counterpart of Linear Temporal Logic (LTL). Unfortunately, the tool support for MITL verification is still lacking to this day. In this paper, we propose a new construction from MITL to timed automata via very-weak one-clock alternating timed automata. Our construction subsumes the well-known construction from LTL to Büchi automata by Gastin and Oddoux and yet has the additional benefits of being compositional and integrating easily with existing tools. We implement the construction in our new tool MightyL and report on experiments using Uppaal and LTSmin as back-ends

Secondary organic aerosol formation from isoprene photooxidation during cloud condensation-evaporation cycles

Abstract. The impact of cloud events on isoprene secondary organic aerosol (SOA) formation has been studied from an isoprene ∕ NOx ∕ light system in an atmospheric simulation chamber. It was shown that the presence of a liquid water cloud leads to a faster and higher SOA formation than under dry conditions. When a cloud is generated early in the photooxidation reaction, before any SOA formation has occurred, a fast SOA formation is observed with mass yields ranging from 0.002 to 0.004. These yields are 2 and 4 times higher than those observed under dry conditions. When the cloud is generated at a later photooxidation stage, after isoprene SOA is stabilized at its maximum mass concentration, a rapid increase (by a factor of 2 or higher) of the SOA mass concentration is observed. The SOA chemical composition is influenced by cloud generation: the additional SOA formed during cloud events is composed of both organics and nitrate containing species. This SOA formation can be linked to the dissolution of water soluble volatile organic compounds (VOCs) in the aqueous phase and to further aqueous phase reactions. Cloud-induced SOA formation is experimentally demonstrated in this study, thus highlighting the importance of aqueous multiphase systems in atmospheric SOA formation estimations. The authors thank Arnaud Allanic, Sylvain Ravier, Pascal Renard and Pascal Zapf for their contributions in the experiments. The authors also acknowledge the institutions that have provided financial support: the French National Institute for Geophysical Research (CNRS-INSU) within the LEFE-CHAT program through the project “Impact de la chimie des nuages sur la formation d’aérosols organiques secondaires dans l’atmosphère” and the French National Agency for Research (ANR) project CUMULUS ANR-2010-BLAN-617-01. This work was also supported by the EC within the I3 project “Integrating of European Simulation Chambers for Investigating Atmospheric Processes” (EUROCHAMP-2, contract no. 228335). The authors thank the MASSALYA instrumental platform (Aix Marseille Université, lce.univ-amu.fr) for the analysis and measurements used in this paper.This is the final version of the article. It first appeared from Copernicus Publications via http://dx.doi.org/10.5194/acp-16-1747-201

Indoor residual spraying for malaria control in sub-Saharan Africa 1997 to 2017: an adjusted retrospective analysis

Indoor residual spraying (IRS) is a key tool for controlling and eliminating malaria by targeting vectors. To support the development of effective intervention strategies it is important to understand the impact of vector control tools on malaria incidence and on the spread of insecticide resistance. In 2006, the World Health Organization (WHO) stated that countries should report on coverage and impact of IRS, yet IRS coverage data are still sparse and unspecific. Here, the subnational coverage of IRS across sub‑Saharan Africa for the four main insecticide classes from 1997 to 2017 were estimated

Modified Gellan Gum hydrogels with tunable physical and mechanical properties

Gellan Gum (GG) has been recently proposed for tissue engineering applications. GG hydrogels are produced by physical crosslinking methods induced by temperature variation or by the presence of divalent cations. However, physical crosslinking methods may yield hydrogels that become weaker in physiological conditions due to the exchange of divalent cations by monovalent ones. Hence, this work presents a new class of GG hydrogels crosslinkable by both physical and chemical mechanisms. Methacrylate groups were incorporated in the GG chain, leading to the production of a methacrylated Gellan Gum (MeGG) hydrogel with highly tunable physical and mechanical properties. The chemical modification was confirmed by proton nuclear magnetic resonance (1H NMR) and Fourier transform infrared spectroscopy (FTIR-ATR). The mechanical properties of the developed hydrogel networks, with Young's modulus values between 0.15 and 148 kPa, showed to be tuned by the different crosslinking mechanisms used. The in vitro swelling kinetics and hydrolytic degradation rate were dependent on the crosslinking mechanisms used to form the hydrogels. Three-dimensional (3D) encapsulation of NIH-3T3 fibroblast cells in MeGG networks demonstrated in vitro biocompatibility confirmed by high cell survival. Given the highly tunable mechanical and degradation properties of MeGG, it may be applicable for a wide range of tissue engineering approaches.This research was funded by the US Army Engineer Research and Development Center, the Institute for Soldier Nanotechnology, the NIH (HL092836, DE019024, EB007249), and the National Science Foundation CAREER award (AK). This work was partially supported by FCT, through funds from the POCTI and/or FEDER programs and from the European Union under the project NoE EXPERTISSUES (NMP3-CT-2004-500283). DFC acknowledges the Foundation for Science and Technology (FCT), Portugal and the MIT-Portugal Program for personal grant SFRH/BD/37156/2007. HS was supported by a Samsung Scholarship. SS acknowledges the postdoctoral fellowship awarded by Fonds de Recherche sur la Nature et les Technologies (FQRNT), Quebec, Canada. We would like to thank Dr. Che Hutson for scientific discussions

Mild folate deficiency induces genetic and epigenetic instability and phenotype changes in prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Folate (vitamin B9) is essential for cellular proliferation as it is involved in the biosynthesis of deoxythymidine monophosphate (dTMP) and s-adenosylmethionine (AdoMet). The link between folate depletion and the genesis and progression of cancers of epithelial origin is of high clinical relevance, but still unclear. We recently demonstrated that sensitivity to low folate availability is affected by the rate of polyamine biosynthesis, which is prominent in prostate cells. We, therefore, hypothesized that prostate cells might be highly susceptible to genetic, epigenetic and phenotypic changes consequent to folate restriction.</p> <p>Results</p> <p>We studied the consequences of long-term, mild folate depletion in a model comprised of three syngenic cell lines derived from the transgenic adenoma of the mouse prostate (TRAMP) model, recapitulating different stages of prostate cancer; benign, transformed and metastatic. High-performance liquid chromatography analysis demonstrated that mild folate depletion (100 nM) sufficed to induce imbalance in both the nucleotide and AdoMet pools in all prostate cell lines. Random oligonucleotide-primed synthesis (ROPS) revealed a significant increase in uracil misincorporation and DNA single strand breaks, while spectral karyotype analysis (SKY) identified five novel chromosomal rearrangements in cells grown with mild folate depletion. Using global approaches, we identified an increase in CpG island and histone methylation upon folate depletion despite unchanged levels of total 5-methylcytosine, indicating a broad effect of folate depletion on epigenetic regulation. These genomic changes coincided with phenotype changes in the prostate cells including increased anchorage-independent growth and reduced sensitivity to folate depletion.</p> <p>Conclusions</p> <p>This study demonstrates that prostate cells are highly susceptible to genetic and epigenetic changes consequent to mild folate depletion as compared to cells grown with supraphysiological amounts of folate (2 μM) routinely used in tissue culture. In addition, we elucidate for the first time the contribution of these aspects to consequent phenotype changes in epithelial cells. These results provide a strong rationale for studying the effects of folate manipulation on the prostate <it>in vivo</it>, where cells might be more sensitive to changes in folate status resulting from folate supplementation or antifolate therapeutic approaches.</p

From theoretical concepts to policies and applied programmes: the landscape of integration of oral health in primary care

Background: Despite its importance, the integration of oral health into primary care is still an emerging practice in the field of health care services. This scoping review aims to map the literature and provide a summary on the conceptual frameworks, policies and programs related to this concept. Methods: Using the Levac et al. six-stage framework, we performed a systematic search of electronic databases, organizational websites and grey literature from 1978 to April 2016. All relevant original publications with a focus on the integration of oral health into primary care were retrieved. Content analyses were performed to synthesize the results. Results: From a total of 1619 citations, 67 publications were included in the review. Two conceptual frameworks were identified. Policies regarding oral heath integration into primary care were mostly oriented toward common risk factors approach and care coordination processes. In general, oral health integrated care programs were designed in the public health sector and based on partnerships with various private and public health organizations, governmental bodies and academic institutions. These programmes used various strategies to empower oral health integrated care, including building interdisciplinary networks, training nondental care providers, oral health champion modelling, enabling care linkages and care coordinated process, as well as the use of e-health technologies. The majority of studies on the programs outcomes were descriptive in nature without reporting long-term outcomes. Conclusions: This scoping review provided a comprehensive overview on the concept of integration of oral health in primary care. The findings identified major gaps in reported programs outcomes mainly because of the lack of related research. However, the results could be considered as a first step in the development of health care policies that support collaborative practices and patient-centred care in the field of primary care sector