[10]-Gingerol Affects Multiple Metastatic Processes and Induces Apoptosis in MDAMB- 231 Breast Tumor Cells.
Triple Negative Breast Cancer (TNBC) represents the approximately 15% of breast cancers that lack expression of Estrogen (ER) and Progesterone Receptors (PR) and do not exhibit amplification of the human epidermal growth factor receptor 2 (HER2) gene, imposing difficulties to treatment. Interactions between tumor cells and their microenvironment facilitate tumor cell invasion in the surrounding tissues, intravasation through newly formed vessels, and dissemination to form metastasis. To treat metastasis from breast and many other cancer types, chemotherapy is one of the most extensively used methods. However, its efficacy and safety remain a primary concern, as well as its toxicity and other side effects. Thus, there is increasing interest in natural antitumor agents. In a previous work, we have demonstrated that [10]-gingerol is able to revert malignant phenotype in breast cancer cells in 3D culture and, moreover, to inhibit the dissemination of TNBC to multiple organs including lung, bone and brain, in spontaneous and experimental in vivo metastasis assays in mouse model. This work aims to investigate the in vitro effects of [10]-gingerol, using human MDA-MB-231TNBC cells, in comparison to non-tumor MCF-10A breast cells, in order to understand the antitumor and antimetastatic effects found in vivo and in a 3D environment. We investigated different steps of the metastatic process in vitro, such as cell migration, invasion, adhesion and MMP activity. In addition, we analyzed the anti-apoptotic and genotoxic effects of [10]-gingerol using PEAnnexin, DNA fragmentation, TUNEL and comet assays, respectively. [10]-gingerol was able to inhibit cell adhesion, migration, invasion and to induce apoptosis more effectively in TNBC cells, when compared to non-tumor cells, demonstrating that these mechanisms can be involved in the antitumor and antimetastatic effects of [10]-gingerol, found both in 3D culture and in vivo. Taken together, results found here are complementary to previous studies of our group and others and demonstrate that additional mechanisms, besides apoptotic cell death, is used by [10]-gingerol to accomplish its antitumor and antimetastatic effects. Our results indicate a potential for this natural compound as an antitumor molecule or as an adjuvant for chemotherapeutics already used in the clinic.


Experimental retrieval of the kinetic parameters of a dye in a solid film.
Effects of a solid matrix on the dye kinetic parameters for Rh800 were experimentally studied. Saturation intensity dependencies were measured with a seeding pulse amplification method using a picosecond and a femtosecond white light supercontinuum source. The kinetic parameters were obtained by fitting experimental dependencies with Yee's finite-difference time-domain model coupled to the rate equations of the 4-level Rh800-system. The comparison of these parameters (Rh800-solid host) with liquid host parameters revealed a slight change of the radiative lifetime and a strong change of the non-radiative decay rate. This experimentally determined model enables predictive simulations of time-domain responses of active metamaterials.


Biomarker Assessment of HR Deficiency, Tumor BRCA1/2 Mutations, and CCNE1 Copy Number in Ovarian Cancer: Associations with Clinical Outcome Following Platinum Monotherapy.
The current study evaluated three biomarkers [homologous recombination deficiency (HRD), tumor BRCA1/2 (tBRCA) mutations, and CCNE1 copy-number variation (CNV)] in ovarian tumors from patients enrolled on the SCOTROC4 clinical trial for associations with outcome following carboplatin monotherapy. Ovarian tumors (n = 250), with high-grade serous (HGSOC) subgroup analysis (n = 179) were classified as HRD positive (HRD score ≥42 or tBRCA mutation) and as CCNE1 amplification positive (CCNE1 CNV score >2.4). Seventy-four (30%) tumors were HRD positive, including 34 (14%) with tBRCA mutations. Forty-seven (19%) were CCNE1 amplification positive, all of which were tBRCA wild-type. HRD and tBRCA, but not CCNE1 amplification, were significantly associated with CA125 complete response in the entire cohort (HRD, P = 0.00015; tBRCA P = 0.0096), and the HGSOC subgroup (HRD, P = 0.0016; tBRCA P = 0.032). HRD and lack of CCNE1 amplification were associated with improved progression-free survival (PFS) and overall survival (OS) in the full cohort and HGSOC subgroup (HRD, P = 0.00021; CCNE1 status P = 0.038). HRD remained significant for OS and PFS after adjusting for clinical factors, while CCNE1 status only remained significant for PFS. Patients with HRD-positive tumors had greater PFS and OS benefit from platinum dose intensification than HRD-negative tumors (P = 0.049 and P = 0.035, respectively). An alternative exploratory HRD score threshold (≥33 or tBRCA mutation) was also significantly associated with both PFS and OS in the HGSOC subset.Implications: HRD, tumor BRCA1/2 mutations, and absence of CCNE1 amplification are associated with improved survival of ovarian cancer patients treated with platinum monotherapy and HRD-positive patients may benefit from platinum dose intensification. Mol Cancer Res; 16(7); 1103-11. ©2018 AACR.


HOST-SWITCHING EVENTS IN LITOMOSOIDES CHANDLER, 1931 (FILARIOIDEA: ONCHOCERCIDAE) ARE NOT RAMPANT BUT CLADE DEPENDENT.
The genus Litomosoides Chandler, 1931, includes species that as adults occur in the thoracic and abdominal cavity of mammalian hosts and are presumably vectored by mites. The vertebrate hosts include a variety of Neotropical mammals such as phyllostomid and mormoopid bats; cricetid, sciurid, and hystricognath rodents; and didelphid marsupials. It has been suggested that Litomosoides is not a monophyletic group and that rampant horizontal transfer explains their presence in disparate groups of mammals. Herein we present a phylogenetic reconstruction including mitochondrial genes of 13 vouchered species. This phylogeny is used to reconstruct the evolutionary history of these parasites and the ancestral states of key characters used in species classification, namely, the configuration of the spicules. The historical association of these filarioids with 6 groups of mammals, as well as their ancestral geographic distributions, were reconstructed using Bayesian statistical approaches comparing alternative models of biogeography and evolution and fossil states in selected nodes of the phylogeny. The optimal reconstruction suggests a model of dispersal, extinction, and cladogenesis (DEC) driving the evolution of Litomosoides; the results suggest an origin of Litomosoides in South America and association of ancestors with phyllostomids, and strong evidence of at least 2 host-switching events: 1 of these involving cricetid rodents and the other mormoopid bats. The latter event included a simultaneous geographic expansion of the parasite lineage across South and North America. The host-switching event from phyllostomid bats into cricetid rodents occurred once these rodents diversified across South America; subsequent diversification of the latter clade resulted in 2 branches, each showing expansion of the parasites back into North America. This result suggests that both parasites and cricetid rodents established an association in South America, underwent diversification, and then dispersed into North America. Further, this clade of cricetid-dwelling species includes parasites featuring the "sigmodontis" spicule type. The identification of a single host-switching event involving the disparate lineages of Chiroptera and Rodentia offers a framework to reconstruct the gene evolution and diversification of this lineage after the host-switching event. This will help in predicting the ability of these parasites to infect sympatric mammals.


Myosin phosphorylation and cyclic adenosine 3',5'-monophosphate in relaxation of arterial smooth muscle by vasodilators.
Recent evidence indicates that contraction of vascular smooth muscle may be regulated by two calcium-dependent mechanisms: activation of myosin kinase, and calcium binding to a second, unknown regulatory site. This hypothesis implies that vasodilators could modify vascular tone by several mechanisms, including inactivation of myosin kinase. Since relaxation of the carotid artery following agonist removal may occur when myosin phosphorylation is at resting levels, we could determine whether dephosphorylation of myosin is necessarily involved in the molecular mechanisms mediating relaxation in response to vasodilators. The relaxant effects of adenosine, 3-isobutyl-1-methylxanthine, forskolin, sodium nitroprusside, and 8-bromo-cGMP were tested under conditions where myosin phosphorylation was at basal levels (0.08 +/- 0.02 mol Pi/mol light chain). All of these agents increased the rate of relaxation in nonsteady state experiments where relaxation was induced by stimulus washout. Steady state dose-response curves were obtained for forskolin and 8-bromo-cGMP in the presence of basal myosin phosphorylation. Forskolin caused a dose-dependent increase in cAMP levels at a rate consistent with a cause and effect relationship between relaxation and total tissue cAMP content. Both drugs relaxed the muscles, with no detectable change in myosin phosphorylation. Therefore, dephosphorylation of myosin is not a necessary event in the molecular mechanism of several vasodilators, including some which presumably act via cyclic nucleotides.


Crystal Structure of the Human Pol α B Subunit in Complex with the C-terminal Domain of the Catalytic Subunit.
In eukaryotic DNA replication, short RNA-DNA hybrid primers synthesized by primase-DNA polymerase α (Prim-Pol α) are needed to start DNA replication by the replicative DNA polymerases, Pol δ and Pol ϵ. The C terminus of the Pol α catalytic subunit (p180C) in complex with the B subunit (p70) regulates the RNA priming and DNA polymerizing activities of Prim-Pol α. It tethers Pol α and primase, facilitating RNA primer handover from primase to Pol α. To understand these regulatory mechanisms and to reveal the details of human Pol α organization, we determined the crystal structure of p70 in complex with p180C. The structured portion of p70 includes a phosphodiesterase (PDE) domain and an oligonucleotide/oligosaccharide binding (OB) domain. The N-terminal domain and the linker connecting it to the PDE domain are disordered in the reported crystal structure. The p180C adopts an elongated asymmetric saddle shape, with a three-helix bundle in the middle and zinc-binding modules (Zn1 and Zn2) on each side. The extensive p180C-p70 interactions involve 20 hydrogen bonds and a number of hydrophobic interactions resulting in an extended buried surface of 4080 Å(2). Importantly, in the structure of the p180C-p70 complex with full-length p70, the residues from the N-terminal to the OB domain contribute to interactions with p180C. The comparative structural analysis revealed both the conserved features and the differences between the human and yeast Pol α complexes.


National health policy-makers' views on the clarity and utility of Countdown to 2015 country profiles and reports: findings from two exploratory qualitative studies.
The use of sets of indicators to assess progress has become commonplace in the global health arena. Exploratory research has suggested that indicators used for global monitoring purposes can play a role in national policy-making, however, the mechanisms through which this occurs are poorly understood. This article reports findings from two qualitative studies that aimed to explore national policy-makers' interpretation and use of indicators from country profiles and reports developed by Countdown to 2015. An initial study aimed at exploring comprehension of Countdown data was conducted at the 2010 joint Women Deliver/Countdown conference. A second study was conducted at the 64th World Health Assembly in 2011, specifically targeting national policy-makers. Semi-structured interviews were carried out with 29 and 22 participants, respectively, at each event. Participants were asked about their understanding of specific graphs and indicators used or proposed for use in Countdown country profiles, and their perception of how such data can inform national policy-making. Responses were categorised using a framework analysis. Respondents in both studies acknowledged the importance of the profiles for tracking progress on key health indicators in and across countries, noting that they could be used to highlight changes in coverage, possible directions for future policy, for lobbying finance ministers to increase resources for health, and to stimulate competition between neighbouring or socioeconomically similar countries. However, some respondents raised questions about discrepancies between global estimates and data produced by national governments, and some struggled to understand the profile graphs shown in the absence of explanatory text. Some respondents reported that use of Countdown data in national policy-making was constrained by limited awareness of the initiative, insufficient detail in the country profiles to inform policy, and the absence of indicators felt to be more appropriate to their own country contexts. The two studies emphasise the need for country consultations to ensure that national policy-makers understand how to interpret and use tools like the Countdown profile for planning purposes. They make clear the value of qualitative research for refining tools used to promote accountability, and the need for country level Countdown-like processes.


Robust detection of dynamic community structure in networks.
We describe techniques for the robust detection of community structure in some classes of time-dependent networks. Specifically, we consider the use of statistical null models for facilitating the principled identification of structural modules in semi-decomposable systems. Null models play an important role both in the optimization of quality functions such as modularity and in the subsequent assessment of the statistical validity of identified community structure. We examine the sensitivity of such methods to model parameters and show how comparisons to null models can help identify system scales. By considering a large number of optimizations, we quantify the variance of network diagnostics over optimizations ("optimization variance") and over randomizations of network structure ("randomization variance"). Because the modularity quality function typically has a large number of nearly degenerate local optima for networks constructed using real data, we develop a method to construct representative partitions that uses a null model to correct for statistical noise in sets of partitions. To illustrate our results, we employ ensembles of time-dependent networks extracted from both nonlinear oscillators and empirical neuroscience data.


Vibroacoustic disease: biological effects of infrasound and low-frequency noise explained by mechanotransduction cellular signalling.
At present, infrasound (0-20 Hz) and low-frequency noise (20-500 Hz) (ILFN, 0-500 Hz) are agents of disease that go unchecked. Vibroacoustic disease (VAD) is a whole-body pathology that develops in individuals excessively exposed to ILFN. VAD has been diagnosed within several professional groups employed within the aeronautical industry, and in other heavy industries. However, given the ubiquitous nature of ILFN and the absence of legislation concerning ILFN, VAD is increasingly being diagnosed among members of the general population, including children. VAD is associated with the abnormal growth of extra-cellular matrices (collagen and elastin), in the absence of an inflammatory process. In VAD, the end-product of collagen and elastin growth is reinforcement of structural integrity. This is seen in blood vessels, cardiac structures, trachea, lung, and kidney of both VAD patients and ILFN-exposed animals. VAD is, essentially, a mechanotransduction disease. Inter- and intra-cellular communication is achieved through both biochemical and mechanotranduction signalling. When the structural components of tissue are altered, as is seen in ILFN-exposed specimens, the mechanically mediated signalling is, at best, impaired. Common medical diagnostic tests, such as EKG, EEG, as well as many blood chemistry analyses, are based on the mal-function of biochemical signalling processes. VAD patients typically present normal values for these tests. However, when echocardiography, brain MRI or histological studies are performed, where structural changes can be identified, all consistently show significant changes in VAD patients and ILFN-exposed animals. Frequency-specific effects are not yet known, valid dose-responses have been difficult to identify, and large-scale epidemiological studies are still lacking.


Serological and molecular investigation of human brucellosis in participants of Famenin brucellosis cohort study, Hamadan, Iran.
Brucella is an intracellular pathogen that causes brucellosis in humans and animals. This study aimed to assess the results of brucellosis seroprevalence among participants of the Famenin brucellosis cohort with molecular investigation technique and determine Brucella-approved species. Following the first phase of the Famenin brucellosis cohort in 2016 which investigated the seroprevalence of brucellosis among 2367 participants in Famenin city, a total of 575 people including all seropositive and some seronegative people were examined again by wright serological tests in 2019. The PCR assay was accomplished on all cases that have wright titers ≥ 1/20 for tracing Brucella DNA using BCSP31 target gene and IS711 locus. Out of 575 studied cases, 145 people had wright titers ≥ 1/20. The PCR reactions of these 145 blood samples were positive in 63/145 (43.44%) tested samples using primers (B4/B5) for Brucella genus detection. In the second PCR assay using specific-primers for Brucella abortus and Brucella melitensis, 18/63 (28.57%) of the samples were diagnosed as B. abortus, and 18/63 (28.57%) were diagnosed as B. melitensis. In this study, using the selected specific genes for the diagnosis of Brucella in the genus and species levels, the PCR technique was evaluated as a promising method for the rapid and safe detection of brucellosis besides the serological test for more accurate detection of brucellosis especially in cases that are not definitive.


Helminth burden and ecological factors associated with alterations in wild host gastrointestinal microbiota.
Infection by gastrointestinal helminths of humans, livestock and wild animals is common, but the impact of such endoparasites on wild hosts and their gut microbiota represents an important overlooked component of population dynamics. Wild host gut microbiota and endoparasites occupy the same physical niche spaces with both affecting host nutrition and health. However, associations between the two are poorly understood. Here we used the commonly parasitized European shag (Phalacrocorax aristotelis) as a model wild host. Forty live adults from the same colony were sampled. Endoscopy was employed to quantify helminth infection in situ. Microbiota from the significantly distinct proventriculus (site of infection), cloacal and faecal gastrointestinal tract microbiomes were characterised using 16S rRNA gene-targeted high-throughput sequencing. We found increasingly strong associations between helminth infection and microbiota composition progressing away from the site of infection, observing a pronounced dysbiosis in microbiota when samples were partitioned into high- and low-burden groups. We posit this dysbiosis is predominately explained by helminths inducing an anti-inflammatory environment in the proventriculus, diverting host immune responses away from themselves. This study, within live wild animals, provides a vital foundation to better understand the mechanisms that underpin the three-way relationship between helminths, microbiota and hosts.


Selective activation of ATF6 and PERK endoplasmic reticulum stress signaling pathways prevent mutant rhodopsin accumulation.
Many rhodopsin mutations that cause retinitis pigmentosa produce misfolded rhodopsin proteins that are retained within the endoplasmic reticulum (ER) and cause photoreceptor cell death. Activating transcription factor 6 (ATF6) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) control intracellular signaling pathways that maintain ER homeostasis. The aim of this study was to investigate how ATF6 and PERK signaling affected misfolded rhodopsin in cells, which could identify new molecular therapies to treat retinal diseases associated with ER protein misfolding. To examine the effect of ATF6 on rhodopsin, wild-type (WT) or mutant rhodopsins were expressed in cells expressing inducible human ATF6f, the transcriptional activator domain of ATF6. Induction of ATF6f synthesis rapidly activated downstream genes. To examine PERK's effect on rhodopsin, WT or mutant rhodopsins were expressed in cells expressing a genetically altered PERK protein, Fv2E-PERK. Addition of the dimerizing molecule (AP20187) rapidly activated Fv2E-PERK and downstream genes. By use of these strategies, it was examined how selective ATF6 or PERK signaling affected the fate of WT and mutant rhodopsins. ATF6 significantly reduced T17M, P23H, Y178C, C185R, D190G, K296E, and S334ter rhodopsin protein levels in the cells with minimal effects on monomeric WT rhodopsin protein levels. By contrast, the PERK pathway reduced both levels of WT, mutant rhodopsins, and many other proteins in the cell. This study indicates that selectively activating ATF6 or PERK prevents mutant rhodopsin from accumulating in cells. ATF6 signaling may be especially useful in treating retinal degenerative diseases arising from rhodopsin misfolding by preferentially clearing mutant rhodopsin and abnormal rhodopsin aggregates.


Optimal collimation of misaligned optical systems by concentering primary field aberrations.
A collimation method of misaligned optical systems is proposed. The method is based on selectively nullifying main alignment-driven aberration components. This selective compensation is achieved by the optimal adjustment of chosen alignment parameters. It is shown that this optimal adjustment can be obtained by solving a linear matrix equation of the low-order alignment-driven terms of primary field aberrations. A significant result from the adjustment is to place the centers of the primary field aberrations, initially scattered over the field due to misalignment, to a desired common field location. This aberration concentering naturally results in recovery of image quality across the field of view. Error analyses and robustness tests show the method's feasibility in efficient removal of alignment-driven aberrations in the face of measurement and model uncertainties. The extension of the method to the collim ion of a misaligned system with higher-order alignment-driven aberrations is also shown.


Evaluating optimal superficial limb perfusion at different angles using non-invasive micro-lightguide spectrophotometry.
It is common practice to elevate the limbs postoperatively to reduce oedema and hence optimise perfusion and facilitate rehabilitation. However, elevation may be counterproductive as it reduces the mean perfusion pressure. There are no clear data on the optimal position of the limbs even in normal subjects. The optimal position of limbs was investigated in 25 healthy subjects using a non-invasive micro-lightguide spectrophotometry system "O2C", which indirectly measures skin and superficial tissue perfusion through blood flow, oxygen saturation and relative haemoglobin concentration. We found a reduction in skin and superficial tissue blood flow of 17% (p=0.0001) on arm elevation (180° shoulder flexion) as compared to heart level and an increase in skin and superficial tissue blood flow of 25% (p=0.02) on forearm elevation of 45°. Lower limb skin and superficial tissue blood flow decreased by 15% (p=0.004) on elevation to 47 cm and by 70% on dependency (p=0.0001) compared to heart level. However, on elevation of the lower limb there was also a 28% reduction in superficial venous pooling (p=0.0001) compared to heart level. In the normal limb, the position for optimal superficial perfusion of the upper limb is with the arm placed at heart level and forearm at 45°. In the lower limb the optimal position for superficial perfusion would be at heart level. However, some degree of elevation may be useful if there is an element of venous congestion.


Controlling Knee Swing Initiation and Ankle Plantarflexion With an Active Prosthesis on Level and Inclined Surfaces at Variable Walking Speeds.
Improving lower-limb prostheses is important to enhance the mobility of amputees. The purpose of this paper is to introduce an impedance-based control strategy (consisting of four novel algorithms) for an active knee and ankle prosthesis and test its generalizability across multiple walking speeds, walking surfaces, and users. The four algorithms increased ankle stiffness throughout stance, decreased knee stiffness during terminal stance, as well as provided powered ankle plantarflexion and knee swing initiation through modifications of equilibrium positions of the ankle and knee, respectively. Seven amputees (knee disarticulation and transfemoral levels) walked at slow, comfortable, and hurried speeds on level and inclined (10°) surfaces. The prosthesis was tuned at their comfortable level ground walking speed. We further quantified trends in prosthetic knee and ankle kinematics, and kinetics across conditions. Subjects modulated their walking speed by ±25% (average) from their comfortable speeds. As speed increased, increasing ankle angles and velocities as well as stance phase ankle power and plantarflexion torque were observed. At slow and comfortable speeds, plantarflexion torque was increased on the incline. At slow and comfortable speeds, stance phase positive knee power was increased and knee torque more flexor on the incline. As speed increased, knee torque became less flexor on the incline. These algorithms were shown to generalize well across speed, produce gait mechanics that compare favorably with non-amputee data, and display evidence of scalable device function. They have the potential to reduce the challenge of clinically configuring such devices and increase their viability during daily use.


Late morphological progression of a dissecting basilar artery aneurysm after staged bilateral vertebral artery occlusion: case report.
The authors present a patient who experienced late (5-year follow-up) morphological progression of a dissecting aneurysm of the distal basilar artery after treatment with a combined microsurgical and neuroendovascular Hunterian strategy. In addition to postulating about the possible reasons underlying the evolution of this lesion, the role of stenting is discussed. The patient was 37 years old when she suffered a subarachnoid hemorrhage from spontaneous basilar artery dissection. At the time of the hemorrhage, minimal aneurysmal enlargement was noted angiographically, and she was therefore treated nonoperatively. On reimaging 5 months later, massive enlargement of the aneurysm was noted. The patient was treated with staged bilateral vertebral artery sacrifice using a combination of microsurgical and neuroendovascular techniques. The dominant vertebral artery was clip-ligated distal to the posteroinferior cerebellar artery, whereas the contralateral vertebral artery was coil-occluded cervically 1 week later. Despite the patient remaining asymptomatic, follow-up angiography 5 years after the initial hemorrhage revealed further enlargement of the aneurysm as well as a newly discovered inferiorly projecting daughter sac measuring 5 mm in diameter. Clearly, certain aneurysms exist for which indirect approaches involving hemodynamic attenuation fail to prevent progression. With greater refinements in stent technology, such lesions may be more effectively treated.


Side-Effects and Social Norms Influencing Family Planning Use in Nepal.
Background Effective family planning (FP) programs promote modern contraceptives and help individuals achieve their reproductive goals. Despite Nepal's relatively high contraceptive prevalence rate (50%), 27% of married women have an unmet need for FP, and almost half of Nepalese women give birth by the age of 20. This formative study explored the factors that influence the use of contraceptives in Nepal. Objective To provide information about barriers to family planning use, general fertility awareness, and barriers to family planning use among difficult to reach groups communities. Method This qualitative study was implemented in five districts in Nepal. A total of 36 focus group discussions, 18 participatory group discussions, and 144 in-depth interviews were conducted. Participants included young married women, men and FP service providers in eight village development committees and two municipalities. The interviews were digitally recorded, transcribed in Nepali and then translated into English. Data was organized using Atlas Ti 7 and coded using a thematic analysis. Result Four key themes emerged from the analyses: 1) limited knowledge on fertility awareness and family planning methods, 2) religious-cultural factors including social norms impediments contraceptives use, 3) fear of side-effects, myths and misconceptions about modern contraceptives, and 4) structural barriers such as limited family planning services, and lack of same gender providers make it difficult for many women to access modern contraceptives services. Conclusion Continuing Nepal's recent gains in contraceptives prevalence rate will require strong educational interventions addressing fertility awareness, social norms around son preference, dispelling fear of side-effects while increasing the family planning method-mix. Health service providers should continue counseling clients on the management of potential side-effects and ensure accurate information about modern contraceptives.


Global Health Perspectives on Cigarette Butts and the Environment.
Cigarette butts, whuch are also known as tobacco product waste (TPW), are the single most collected item in environmental trash cleanups worldwide. This study used an online survey tool (Qualtrics) to assess knowledge, attitudes, and perceptions regarding this issue among individuals representing the Framework Convention Alliance (FCA). The FCA has about 680 members on its listserv, including non-governmental tobacco control advocacy groups that support the implementation of the World Health Organization's (WHO) Framework Convention on Tobacco Control (FCTC). Respondents (n = 65) represented countries from all six WHO regions. The majority (82%) had heard the term TPW, and they all considered TPW as an environmental harm at some level. Additionally, 29% of respondents failed to identify that "cigarette filters make smoking easier". Most (73%) correctly identified TPW components; however, fewer (60%) correctly identified the composition of cigarette butts. The majority (57%) were unfamiliar with Extended Producer Responsibility (EPR) and Product Stewardship (PS) as possible environmental intervention strategies. Respondents expressing opinions concurred that adding a litter fee to fund TPW programs will aid in reducing tobacco use and reduce the environmental impacts of TPW (100%); that prevention, reduction, and mitigation of TPW could be an important part of international tobacco control programs (98%); and, that banning smoking in outdoor venues could reduce TPW (95%). Only 16% reported effective prevention or clean-up efforts in their countries. Weighted rankings revealed that respondents' saw the national government, the tobacco industry, and state governments as the most important in addressing TPW. The results of this research will inform continuing international discussions by the FCTC Conference of the Parties (COP) regarding environmental policies that may be addressed within FCTC obligations.


Accurate description of van der Waals complexes by density functional theory including empirical corrections.
An empirical method to account for van der Waals interactions in practical calculations with the density functional theory (termed DFT-D) is tested for a wide variety of molecular complexes. As in previous schemes, the dispersive energy is described by damped interatomic potentials of the form C6R(-6). The use of pure, gradient-corrected density functionals (BLYP and PBE), together with the resolution-of-the-identity (RI) approximation for the Coulomb operator, allows very efficient computations for large systems. Opposed to previous work, extended AO basis sets of polarized TZV or QZV quality are employed, which reduces the basis set superposition error to a negligible extend. By using a global scaling factor for the atomic C6 coefficients, the functional dependence of the results could be strongly reduced. The "double counting" of correlation effects for strongly bound complexes is found to be insignificant if steep damping functions are employed. The method is applied to a total of 29 complexes of atoms and small molecules (Ne, CH4, NH3, H2O, CH3F, N2, F2, formic acid, ethene, and ethine) with each other and with benzene, to benzene, naphthalene, pyrene, and coronene dimers, the naphthalene trimer, coronene. H2O and four H-bonded and stacked DNA base pairs (AT and GC). In almost all cases, very good agreement with reliable theoretical or experimental results for binding energies and intermolecular distances is obtained. For stacked aromatic systems and the important base pairs, the DFT-D-BLYP model seems to be even superior to standard MP2 treatments that systematically overbind. The good results obtained suggest the approach as a practical tool to describe the properties of many important van der Waals systems in chemistry. Furthermore, the DFT-D data may either be used to calibrate much simpler (e.g., force-field) potentials or the optimized structures can be used as input for more accurate ab initio calculations of the interaction energies.


Use of piracetam improves sickle cell deformability in vitro and in vivo.
Microsieving diluted suspensions of oxygenated sickle cell anaemia (HbSS) cells on polycarbonate filters shows that piracetam improves the red cell deformability in vitro. In vivo an oral intake of 160 mg/kg/day divided in four doses enhances the HbSS cell deformability as actively as it does in in vitro experiments. The drug is also able partially to restore the impaired deformability of physiologically deoxygenated HbSS cells. These findings are consistent with the results of clinical trials, which show that continuous treatment with piracetam reduces the incidence of vaso-occlusive crises in patients with sickle cell disease.


A profile of cortical gray matter volume deficits characteristic of schizophrenia.
Quantitative magnetic resonance imaging (MRI) studies from our laboratory have reported that patients with schizophrenia show a widespread cortical gray matter volume deficit, which is especially pronounced in the prefrontal and anterior superior temporal cortices. The present study compared two separate samples of schizophrenic patients -- 71 men from a Veterans Administration (VA) hospital and a sample of 57 severely ill men from a state hospital (SH) -- in an effort to test whether the pattern of brain volume abnormalities previously observed in VA schizophrenic patients can be generalized to other groups of schizophrenic patients. MRI-derived brain volumes of gray matter, white matter and sulcal cerebrospinal fluid (CSF) in six cortical regions, and CSF in the lateral and third ventricles were computed. All MRI volumes were adjusted for normal variation in head size and age and were expressed as standardized Z-scores, which also permitted structures of different sizes to be compared directly. The two schizophrenic groups displayed similar patterns of volume abnormalities: cortical gray matter but not white matter volume deficits that were widespread but especially notable in the prefrontal and temporal regions. The regional gray matter deficits in the SH group were generally greater than those in the VA group, particularly in the prefrontal and posterior superior temporal regions. Both schizophrenic groups had abnormally large volumes of the cortical sulci and lateral and third ventricles; however, the SH group showed greater enlargements, the most prominent occurring in the ventricles and temporal sulci. The overlapping patterns of cortical gray matter deficits in the two groups provide evidence for generality of this pattern of regional brain volume abnormalities in schizophrenia.


Resolving the relationships of Paleocene placental mammals.
The 'Age of Mammals' began in the Paleocene epoch, the 10 million year interval immediately following the Cretaceous-Palaeogene mass extinction. The apparently rapid shift in mammalian ecomorphs from small, largely insectivorous forms to many small-to-large-bodied, diverse taxa has driven a hypothesis that the end-Cretaceous heralded an adaptive radiation in placental mammal evolution. However, the affinities of most Paleocene mammals have remained unresolved, despite significant advances in understanding the relationships of the extant orders, hindering efforts to reconstruct robustly the origin and early evolution of placental mammals. Here we present the largest cladistic analysis of Paleocene placentals to date, from a data matrix including 177 taxa (130 of which are Palaeogene) and 680 morphological characters. We improve the resolution of the relationships of several enigmatic Paleocene clades, including families of 'condylarths'. Protungulatum is resolved as a stem eutherian, meaning that no crown-placental mammal unambiguously pre-dates the Cretaceous-Palaeogene boundary. Our results support an Atlantogenata-Boreoeutheria split at the root of crown Placentalia, the presence of phenacodontids as closest relatives of Perissodactyla, the validity of Euungulata, and the placement of Arctocyonidae close to Carnivora. Periptychidae and Pantodonta are resolved as sister taxa, Leptictida and Cimolestidae are found to be stem eutherians, and Hyopsodontidae is highly polyphyletic. The inclusion of Paleocene taxa in a placental phylogeny alters interpretations of relationships and key events in mammalian evolutionary history. Paleocene mammals are an essential source of data for understanding fully the biotic dynamics associated with the end-Cretaceous mass extinction. The relationships presented here mark a critical first step towards accurate reconstruction of this important interval in the evolution of the modern fauna.


Automated structure modeling of large protein assemblies using crosslinks as distance restraints.
Crosslinking mass spectrometry is increasingly used for structural characterization of multisubunit protein complexes. Chemical crosslinking captures conformational heterogeneity, which typically results in conflicting crosslinks that cannot be satisfied in a single model, making detailed modeling a challenging task. Here we introduce an automated modeling method dedicated to large protein assemblies ('XL-MOD' software is available at http://aria.pasteur.fr/supplementary-data/x-links) that (i) uses a form of spatial restraints that realistically reflects the distribution of experimentally observed crosslinked distances; (ii) automatically deals with ambiguous and/or conflicting crosslinks and identifies alternative conformations within a Bayesian framework; and (iii) allows subunit structures to be flexible during conformational sampling. We demonstrate our method by testing it on known structures and available crosslinking data. We also crosslinked and modeled the 17-subunit yeast RNA polymerase III at atomic resolution; the resulting model agrees remarkably well with recently published cryoelectron microscopy structures and provides additional insights into the polymerase structure.


Bayes' theorem and diagnostic tests in neuropsychology: interval estimates for post-test probabilities.
Most neuropsychologists are aware that, given the specificity and sensitivity of a test and an estimate of the base rate of a disorder, Bayes' theorem can be used to provide a post-test probability for the presence of the disorder given a positive test result (and a post-test probability for the absence of a disorder given a negative result). However, in the standard application of Bayes' theorem the three quantities (sensitivity, specificity, and the base rate) are all treated as fixed, known quantities. This is very unrealistic as there may be considerable uncertainty over these quantities and therefore even greater uncertainty over the post-test probability. Methods of obtaining interval estimates on the specificity and sensitivity of a test are set out. In addition, drawing and extending upon work by Mossman and Berger (2001), a Monte Carlo method is used to obtain interval estimates for post-test probabilities. All the methods have been implemented in a computer program, which is described and made available (www.abdn.ac.uk/~psy086/dept/BayesPTP.htm). When objective data on the base rate are lacking (or have limited relevance to the case at hand) the program elicits opinion for the pre-test probability.


Micro magnetic resonance angiography of the finger in systemic sclerosis.
To characterize vascular lesions in SSc disease with high-resolution magnetic resonance angiography (Micro-MRA) of the finger. Eight SSc subjects and eight age- and sex-matched healthy controls were recruited for this study. Among the SSc subjects, the mean +/- s.d. age was 54.5 +/- 4.9 yrs, and the mean +/- s.d. duration of disease was 8.3 +/- 8.4 yrs. The numbers of SSc subjects that had telangiectasia, calcinosis and impaired finger flexion were 3, 2 and 3, respectively. The 2D time-of-flight micro-MRA was performed on a 3T clinical MRI scanner using a custom-designed finger coil with an in-plane resolution of 0.16 x 0.21 mm(2) and slice thickness of 1.2 mm. The data for the proper palmar digital artery lumen area, the number of visible dorsal digital veins and a semi-quantitative vascular score, which evaluates the overall integrity of digital vessels, were independently evaluated by two experienced reviewers who were blinded to the status of the subject. Micro-MRA detected significant differences in the digital vasculature between SSc subjects and healthy volunteers. The SSc subjects had a significantly decreased digital artery lumen area (0.13 +/- 0.06 vs 0.53 +/- 0.26 mm(2), P < 0.001), a reduced number of digital veins (0.63 +/- 1.06 vs 3.13 +/- 0.99, P = 0.001) and a lowered overall vascular score (1.75 +/- 1.04 vs 3.5 +/- 0.53, P = 0.001). The study also found that both the digital artery lumen area (Pearson's; r = -0.72, P = 0.044) and vascular scores (Spearman's; rho = -0.75, P = 0.047) of the SSc subjects were inversely correlated with the duration of the disease. Micro-MRA can be used to identify and quantitatively characterize the vascular disease in SSc fingers. The parameters derived from micro-MRA could potentially be used as prospective biomarkers for clinical evaluation.


Arthroscopic abrasion arthroplasty: a review.
Arthroscopic abrasion arthroplasty is an elaborate description for an extensive multiple tissue debridement for patients seeking an alternative to total knee replacement. The operation is palliative, not curative. In patients seeking an alternative to total knee replacement, the definitive operation may be avoided or deferred in a high percentage of patients as many as 5 years. Because the abrasion portion of the operation is accompanied by multiple tissue type debridement, it is not known what clinical benefit the abrasion aspect contributes. Furthermore, no prospective randomized clinical studies have been done and most clinicians reporting on their experience with the procedure have varied the indications, technique, and/or postoperative treatment. Future investigation may answer these clinical questions. It is known that fibrocartilage forms at the abrasion site. The reparative tissue has many of the characteristics of cartilage, but does not have the biomechanical properties of articular cartilage. The fibrocartilage has shown durability for many years confirmed during opportunistic second look arthroscopy. The applications of growth factor science or genetic engineering may provide means of converting the regenerative tissue of abrasion arthroplasty to mature articular cartilage.


Baseline STD prevalence in a community intervention trial of the female condom in Kenya.
We present baseline sexually transmitted disease (STD) prevalence rates from an ongoing intervention trial at Kenyan agricultural sites. After gaining the cooperation of management, we identified six matched pairs of tea, coffee, and flower plantations and enrolled approximately 160 women at each site. Six intervention sites received an information programme and distributed female and male condoms, while six control sites received male condoms only and similar information about them. At clinic visits, we tested participants for cervical gonorrhoea (GC) and Chlamydia trachomatis (CT) by ligase chain reaction on urine specimens, and Trichomonas vaginalis (TV) by culture. The study has 80% power to detect a 10% prevalence difference during follow up, assuming a combined STD prevalence of 20%, 25% loss to follow up and intracluster correlation coefficient (ICC) of 0.03. Participants at intervention and control sites (total 1929) were similar at baseline. Mean age was 33 years, the majority were married, more than half currently used family planning, 78% had never used male condoms, and 9% reported more than one sexual partner in the 3 months before the study. Prevalences of GC, CT, and TV were 2.6%, 3.2%, and 20.4% respectively (23.9% overall), and were similar at intervention and control sites. The ICC for STD prevalence was 0.0011. Baseline STD was associated with unmarried status, non-use of family planning, alcohol use, and more than one recent sexual partner, but the highest odds ratio was 1.5. Baseline results confirm a high prevalence of trichomoniasis and bacterial STD at these Kenyan rural sites. Improved STD management is urgently needed there. Our ongoing female condom intervention trial is feasible as designed.


Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration.
The clinical heterogeneity of frontotemporal dementia (FTD) complicates identification of biomarkers for clinical trials that may be sensitive during the prediagnostic stage. It is not known whether cognitive or behavioural changes during the preclinical period are predictive of genetic status or conversion to clinical FTD. The first objective was to evaluate the most frequent initial symptoms in patients with genetic FTD. The second objective was to evaluate whether preclinical mutation carriers demonstrate unique FTD-related symptoms relative to familial mutation non-carriers. The current study used data from the Genetic Frontotemporal Dementia Initiative multicentre cohort study collected between 2012 and 2018. Participants included symptomatic carriers (n=185) of a pathogenic mutation in chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN) or microtubule-associated protein tau (MAPT) and their first-degree biological family members (n=588). Symptom endorsement was documented using informant and clinician-rated scales. The most frequently endorsed initial symptoms among symptomatic patients were apathy (23%), disinhibition (18%), memory impairments (12%), decreased fluency (8%) and impaired articulation (5%). Predominant first symptoms were usually discordant between family members. Relative to biologically related non-carriers, preclinical MAPT carriers endorsed worse mood and sleep symptoms, and C9orf72 carriers endorsed marginally greater abnormal behaviours. Preclinical GRN carriers endorsed less mood symptoms compared with non-carriers, and worse everyday skills. Preclinical mutation carriers exhibited neuropsychiatric symptoms compared with non-carriers that may be considered as future clinical trial outcomes. Given the heterogeneity in symptoms, the detection of clinical transition to symptomatic FTD may be best captured by composite indices integrating the most common initial symptoms for each genetic group.


First order error propagation of the procrustes method for 3D attitude estimation.
The well-known Procrustes method determines the optimal rigid body motion that registers two point clouds by minimizing the square distances of the residuals. In this paper, we perform the first order error analysis of this method for the 3D case, fully specifying how directional noise in the point clouds affects the estimated parameters of the rigid body motion. These results are much more specific than the error bounds which have been established in numerical analysis. We provide an intuitive understanding of the outcome to facilitate direct use in applications.


The drug and vaccine landscape for neglected diseases (2000-11): a systematic assessment.
In 1975-99, only 1·1% of new therapeutic products had been developed for neglected diseases. Since then, several public and private initiatives have attempted to mitigate this imbalance. We analysed the research and development pipeline of drugs and vaccines for neglected diseases from 2000 to 2011. We searched databases of drug regulatory authorities, WHO, and clinical trial registries for entries made between Jan 1, 2000, and Dec 31, 2011. We defined neglected diseases as malaria, tuberculosis, diarrhoeal diseases, neglected tropical diseases (NTDs; WHO definition), and other diseases of poverty according to common definitions. Of the 850 new therapeutic products registered in 2000-11, 37 (4%) were indicated for neglected diseases, comprising 25 products with a new indication or formulation and eight vaccines or biological products. Only four new chemical entities were approved for neglected diseases (three for malaria, one for diarrhoeal disease), accounting for 1% of the 336 new chemical entities approved during the study period. Of 148,445 clinical trials registered in Dec 31, 2011, only 2016 (1%) were for neglected diseases. Our findings show a persistent insufficiency in drug and vaccine development for neglected diseases. Nevertheless, these and other data show a slight improvement during the past 12 years in new therapeutics development and registration. However, for many neglected diseases, new therapeutic products urgently need to be developed and delivered to improve control and potentially achieve elimination. None.


Gluing Ionic Liquids to Oxide Surfaces: Chemical Anchoring of Functionalized Ionic Liquids by Vapor Deposition onto Cobalt(II) Oxide.
Ionic liquids (IL) hold a great potential as novel electrolytes for applications in electronic materials and energy technology. The functionality of ILs in these applications relies on their interface to semiconducting nanomaterials. Therefore, methods to control the chemistry and structure of this interface are the key to assemble new IL-based electronic and electrochemical materials. Here, we present a new method to prepare a chemically well-defined interface between an oxide and an IL film. An imidazolium-based IL, which is carrying an ester group, is deposited onto cobalt oxide surface by evaporation. The IL binds covalently to the surface by thermally activated cleavage of the ester group and formation of a bridging carboxylate. The anchoring reaction shows high structure sensitivity, which implies that the IL film can be adhered selectively to specific oxide surfaces.


Phonological Planning during Sentence Production: Beyond the Verb.
The current study addresses the extent of phonological planning during spontaneous sentence production. Previous work shows that at articulation, phonological encoding occurs for entire phrases, but encoding beyond the initial phrase may be due to the syntactic relevance of the verb in planning the utterance. I conducted three experiments to investigate whether phonological planning crosses multiple grammatical phrase boundaries (as defined by the number of lexical heads of phrase) within a single phonological phrase. Using the picture-word interference paradigm, I found in two separate experiments a significant phonological facilitation effect to both the verb and noun of sentences like "He opens the gate." I also altered the frequency of the direct object and found longer utterance initiation times for sentences ending with a low-frequency vs. high-frequency object offering further support that the direct object was phonologically encoded at the time of utterance initiation. That phonological information for post-verbal elements was activated suggests that the grammatical importance of the verb does not restrict the extent of phonological planning. These results suggest that the phonological phrase is unit of planning, where all elements within a phonological phrase are encoded before articulation. Thus, consistent with other action sequencing behavior, there is significant phonological planning ahead in sentence production.


Schizophrenia: synthetic strategies and recent advances in drug design.
Schizophrenia is a complex and unpredictable mental disorder which affects several domains of cognition and behaviour. It is a heterogeneous illness characterised by positive, negative, and cognitive symptoms, often accompanied by signs of depression. In this tutorial review, we discuss recent progress in understanding the target sites and mechanisms of action of second-generation antipsychotic drugs. Progress in identifying and defining target sites has been accelerated recently by advances in neuroscience, and newly developed agents that regulate signalling by the main excitatory neurotransmitters in the brain are surveyed. Examples of novel molecules for the treatment of schizophrenia in preclinical and clinical development and their industrial sponsors are highlighted.


Macitentan reduces progression of TGF-β1-induced pulmonary fibrosis and pulmonary hypertension.
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with an unknown cause. Two drugs, nintedanib and pirfenidone, have been shown to slow, but not stop, disease progression. Pulmonary hypertension (PH) is a frequent complication in IPF patients and is associated with poor prognosis. Macitentan is a dual endothelin receptor antagonist that is approved for pulmonary arterial hypertension treatment. We hypothesised that using macitentan to treat animals with pulmonary fibrosis induced by adenoviral vector encoding biologically active transforming growth factor-β1 (AdTGF-β1) would improve the PH caused by chronic lung disease and would limit the progression of fibrosis.Rats (Sprague Dawley) which received AdTGF-β1 were treated by daily gavage of macitentan (100 mg·kg-1·day-1), pirfenidone (0.5% food admix) or a combination from day 14 to day 28. Pulmonary artery pressure (PAP) was measured before the rats were killed, and fibrosis was subsequently evaluated by morphometric measurements and hydroxyproline analysis.AdTGF-β1 induced pulmonary fibrosis associated with significant PH. Macitentan reduced the increase in PAP and both macitentan and pirfenidone stopped fibrosis progression from day 14 to day 28. Macitentan protected endothelial cells from myofibroblast differentiation and apoptosis whereas pirfenidone only protected against fibroblast-to-myofibroblast differentiation. Both drugs induced apoptosis of differentiated myofibroblasts in vitro and in vivoOur results demonstrate that dual endothelin receptor antagonism was effective in both PH and lung fibrosis whereas pirfenidone only affected fibrosis.


Reversible conversion-alloying of Sb2O3 as a high-capacity, high-rate, and durable anode for sodium ion batteries.
Sodium ion batteries are attracting ever-increasing attention for the applications in large/grid scale energy storage systems. However, the research on novel Na-storage electrode materials is still in its infancy, and the cycling stability, specific capacity, and rate capability of the reported electrode materials cannot satisfy the demands of practical applications. Herein, a high performance Sb(2)O(3) anode electrochemically reacted via the reversible conversion-alloying mechanism is demonstrated for the first time. The Sb(2)O(3) anode exhibits a high capacity of 550 mAh g(-1) at 0.05 A g(-1) and 265 mAh g(-1) at 5 A g(-1). A reversible capacity of 414 mAh g(-1) at 0.5 A g(-1) is achieved after 200 stable cycles. The synergistic effect involving conversion and alloying reactions promotes stabilizing the structure of the active material and accelerating the kinetics of the reaction. The mechanism may offer a well-balanced approach for sodium storage to create high capacity and cycle-stable anode materials.


Speech and language therapy for management of chronic cough.
Cough both protects and clears the airway. Cough has three phases: breathing in (inspiration), closure of the glottis, and a forced expiratory effort. Chronic cough has a negative, far-reaching impact on quality of life. Few effective medical treatments for individuals with unexplained (idiopathic/refractory) chronic cough (UCC) are known. For this group, current guidelines advocate the use of gabapentin. Speech and language therapy (SLT) has been considered as a non-pharmacological option for managing UCC without the risks and side effects associated with pharmacological agents, and this review considers the evidence from randomised controlled trials (RCTs) evaluating the effectiveness of SLT in this context. To evaluate the effectiveness of speech and language therapy for treatment of people with unexplained (idiopathic/refractory) chronic cough. We searched the Cochrane Airways Trials Register, CENTRAL, MEDLINE, Embase, CINAHL, trials registries, and reference lists of included studies. Our most recent search was 8 February 2019. We included RCTs in which participants had a diagnosis of UCC having undergone a full diagnostic workup to exclude an underlying cause, as per published guidelines or local protocols, and where the intervention included speech and language therapy techniques for UCC. Two review authors independently screened the titles and abstracts of 94 records. Two clinical trials, represented in 10 study reports, met our predefined inclusion criteria. Two review authors independently assessed risk of bias for each study and extracted outcome data. We analysed dichotomous data as odds ratios (ORs), and continuous data as mean differences (MDs) or geometric mean differences. We used standard methods recommended by Cochrane. Our primary outcomes were health-related quality of life (HRQoL) and serious adverse events (SAEs). We found two studies involving 162 adults that met our inclusion criteria. Neither of the two studies included children. The duration of treatment and length of sessions varied between studies from four sessions delivered weekly, to four sessions over two months. Similarly, length of sessions varied slightly from one 60-minute session and three 45-minute sessions to four 30-minute sessions. The control interventions were healthy lifestyle advice in both studies.One study contributed HRQoL data, using the Leicester Cough Questionnaire (LCQ), and we judged the quality of the evidence to be low using the GRADE approach. Data were reported as between-group difference from baseline to four weeks (MD 1.53, 95% confidence interval (CI) 0.21 to 2.85; participants = 71), revealing a statistically significant benefit for people receiving a physiotherapy and speech and language therapy intervention (PSALTI) versus control. However, the difference between PSALTI and control was not observed between week four and three months. The same study provided information on SAEs, and there were no SAEs in either the PSALTI or control arms. Using the GRADE approach we judged the quality of evidence for this outcome to be low.Data were also available for our prespecified secondary outcomes. In each case data were provided by only one study, therefore there were no opportunities for aggregation; we judged the quality of this evidence to be low for each outcome. A significant difference favouring therapy was demonstrated for: objective cough counts (ratio for mean coughs per hour on treatment was 59% (95% CI 37% to 95%) relative to control; participants = 71); symptom score (MD 9.80, 95% CI 4.50 to 15.10; participants = 87); and clinical improvement as defined by trialists (OR 48.13, 95% CI 13.53 to 171.25; participants = 87). There was no significant difference between therapy and control regarding subjective measures of cough (MD on visual analogue scale of cough severity: -9.72, 95% CI -20.80 to 1.36; participants = 71) and cough reflex sensitivity (capsaicin concentration to induce five coughs: 1.11 (95% CI 0.80 to 1.54; participants = 49) times higher on treatment than on control). One study reported data on adverse events, and there were no adverse events reported in either the therapy or control arms of the study. The paucity of data in this review highlights the need for more controlled trial data examining the efficacy of SLT interventions in the management of UCC. Although a large number of studies were found in the initial search as per protocol, we could include only two studies in the review. In addition, this review highlights that endpoints vary between published studies.The improvements in HRQoL (LCQ) and reduction in 24-hour cough frequency seen with the PSALTI intervention were statistically significant but short-lived, with the between-group difference lasting up to four weeks only. Further studies are required to replicate these findings and to investigate the effects of SLT interventions over time. It is clear that SLT interventions vary between studies. Further research is needed to understand which aspects of SLT interventions are most effective in reducing cough (both objective cough frequency and subjective measures of cough) and improving HRQoL. We consider these endpoints to be clinically important. It is also important for future studies to report information on adverse events.Because of the paucity of data, we can draw no robust conclusions regarding the efficacy of SLT interventions for improving outcomes in unexplained chronic cough. Our review identifies the need for further high-quality research, with comparable endpoints to inform robust conclusions.


A Langevin model for fluctuating contact angle behaviour parametrised using molecular dynamics.
Molecular dynamics simulations are employed to develop a theoretical model to predict the fluid-solid contact angle as a function of wall-sliding speed incorporating thermal fluctuations. A liquid bridge between counter-sliding walls is studied, with liquid-vapour interface-tracking, to explore the impact of wall-sliding speed on contact angle. The behaviour of the macroscopic contact angle varies linearly over a range of capillary numbers beyond which the liquid bridge pinches off, a behaviour supported by experimental results. Nonetheless, the liquid bridge provides an ideal test case to study molecular scale thermal fluctuations, which are shown to be well described by Gaussian distributions. A Langevin model for contact angle is parametrised to incorporate the mean, fluctuation and auto-correlations over a range of sliding speeds and temperatures. The resulting equations can be used as a proxy for the fully-detailed molecular dynamics simulation allowing them to be integrated within a continuum-scale solver.


Risk of involuntary admission among first-generation ethnic minority groups with early psychosis: a retrospective cohort study using health administrative data.
Ethnic minority groups often have more complex and aversive pathways to mental health care. However, large population-based studies are lacking, particularly regarding involuntary hospitalisation. We sought to examine the risk of involuntary admission among first-generation ethnic minority groups with early psychosis in Ontario, Canada. Using health administrative data, we constructed a retrospective cohort (2009-2013) of people with first-onset non-affective psychotic disorder aged 16-35 years. This cohort was linked to immigration data to ascertain migrant status and country of birth. We identified the first involuntary admission within 2 years and compared the risk of involuntary admission for first-generation migrant groups to the general population. To control for the role of migrant status, we restricted the sample to first-generation migrants and examined differences by country of birth, comparing risk of involuntary admission among ethnic minority groups to a European reference. We further explored the role of migrant class by adjusting for immigrant vs refugee status within the migrant cohort. We also explored effect modification of migrant class by ethnic minority group. We identified 15 844 incident cases of psychotic disorder, of whom 19% (n = 3049) were first-generation migrants. Risk of involuntary admission was higher than the general population in five of seven ethnic minority groups. African and Caribbean migrants had the highest risk of involuntary admission (African: risk ratio (RR) = 1.52, 95% CI = 1.34-1.73; Caribbean: RR = 1.58, 95% CI = 1.37-1.82), and were the only groups where the elevated risk persisted when compared to the European reference group within the migrant cohort (African: RR = 1.24, 95% CI = 1.04-1.48; Caribbean: RR = 1.29, 95% CI = 1.07-1.56). Refugee status was independently associated with involuntary admission (RR = 1.16, 95% CI = 1.02-1.32); however, this risk varied by ethnic minority group, with Caribbean refugees having an elevated risk of involuntary admission compared with Caribbean immigrants (RR = 1.72, 95% CI = 1.15-2.58). Our findings are consistent with the international literature showing increased rates of involuntary admission among some ethnic minority groups with early psychosis. Interventions aimed at improving pathways to care could be targeted at these groups to reduce disparities.


Microplastic surface properties affect bacterial colonization in freshwater.
Microplastics are a global concern in aquatic ecology and are readily colonized by bacteria in the environment. There is a lack of information on bacterial colonization of eroded and un-eroded microplastics in freshwater. In this study, six types of microplastics were incubated for 8 weeks in microcosms with water from Lake Erie. Microcosms were inoculated with one of three species: Acinetobacter (A.) calcoaceticus, Burkholderia (B.) cepacia, and Escherichia (E.) coli. These bacterial species are ubiquitous in water bodies associated with human populations. Bacterial surface coverage was determined using electron and fluorescent microscopy. Quantifications of EPS and surface roughness were performed by confocal microscopy and measuring contact angles (θw ) of water droplets on microplastics, respectively. Analyses revealed surface coverage differed among bacterial species and plastic types after 8 weeks. As the study progressed, E. coli remained the most abundant while A. calcoaceticus gradually decreased on most surfaces. Analyses of microcosms revealed polypropylene disks had lower bacterial abundance. Conversely, eroded polypropylene disks had highest bacterial abundance, indicating importance of surface roughness (lower θw values) and surface physicochemical properties of microplastics in bacterial colonization. Our results demonstrated that bacterial colonization of microplastics is affected by both the physicochemical properties of microplastics and the physiological properties of colonizing bacteria.


Food Choice Motives When Purchasing in Organic and Conventional Consumer Clusters: Focus on Sustainable Concerns (The NutriNet-Santé Cohort Study).
The purpose of this study was to examine food choice motives associated with various organic and conventional dietary patterns among 22,366 participants of the NutriNet-Santé study. Dietary intakes were estimated using a food frequency questionnaire. Food choice motives were assessed using a validated 63-item-questionnaire gathered into nine food choice motive dimension scores: "absence of contaminants", "avoidance for environmental reasons", "ethics and environment", "taste", "innovation", "local and traditional production", "price", "health" and "convenience". Five consumers' clusters were identified: "standard conventional food small eaters", "unhealthy conventional food big eaters", "standard organic food small eaters", "green organic food eaters" and "hedonist moderate organic food eaters". Relationships between food choice motive dimension scores and consumers' clusters were assessed using analysis of covariance (ANCOVA) models adjusted for sociodemographic factors. "Green organic food eaters" had the highest mean score for the "health" dimension, while "unhealthy conventional food big eaters" obtained the lowest mean score for the "absence of contaminants" dimension. "Standard organic food small eaters", "green organic food eaters" and "hedonist moderate organic food eaters" had comparable scores for the "taste" dimension. "Unhealthy conventional food big eaters" had the highest mean score for the "price" dimension while "green organic food eaters" had the lowest mean scores for the "innovation" and "convenience" dimensions. These results provide new insights into the food choice motives of diverse consumers' profiles including "green" and "hedonist" eaters.


Overexpression of HER-2 in feline invasive mammary carcinomas: an immunohistochemical survey and evaluation of its prognostic potential.
The role of c-erbB-2 protooncogene status in feline invasive mammary carcinomas (FMCs) was assessed through the HER-2 receptor immunohistochemical expression. The HER-2 overexpression was then correlated with some relevant histologic parameters and with the clinical course of the disease during a 2-year follow-up. Forty-seven FMCs from surgically treated queens were considered. Tumors were classified according to the WHO criteria and stromal or lymphatic invasion (or both) and histologic grading were recorded. The immunohistochemical staining was performed on paraffin sections and a well-defined scoring system based upon numbers of HER-2 receptors expressed on the cell surface was applied according to standard guidelines. Overall survival (OS) distributions were generated with the Kaplan-Meier method. HER-2 overexpression was detected in 28 of the 47 carcinomas (59.6%). This parameter was demonstrated to be significantly correlated with the shorter OS (P = 0.02). However, the HER-2 overexpression did not show significant correlation with histologic type, tumor grading, or presence of lymphatic invasion. Furthermore, the HER-2 overexpression appeared with a higher percentage in FMCs than what is reported in canine or human mammary carcinomas. The significant correlation with a shorter OS suggests a possible role of HER-2 as an additional marker of malignancy in FMCs and as a reliable prognostic indicator. As in the human oncology practice, the identification of the FMCs that overexpress HER-2 may also promote new therapeutic strategies.


Perceptual learning eases crowding by reducing recognition errors but not position errors.
When an observer reports a letter flanked by additional letters in the visual periphery, the response errors (the crowding effect) may result from failure to recognize the target letter (recognition errors), from mislocating a correctly recognized target letter at a flanker location (target misplacement errors), or from reporting a flanker as the target letter (flanker substitution errors). Crowding can be reduced through perceptual learning. However, it is not known how perceptual learning operates to reduce crowding. In this study we trained observers with a partial-report task (Experiment 1), in which they reported the central target letter of a three-letter string presented in the visual periphery, or a whole-report task (Experiment 2), in which they reported all three letters in order. We then assessed the impact of training on recognition of both unflanked and flanked targets, with particular attention to how perceptual learning affected the types of errors. Our results show that training improved target recognition but not single-letter recognition, indicating that training indeed affected crowding. However, training did not reduce target misplacement errors or flanker substitution errors. This dissociation between target recognition and flanker substitution errors supports the view that flanker substitution may be more likely a by-product (due to response bias), rather than a cause, of crowding. Moreover, the dissociation is not consistent with hypothesized mechanisms of crowding that would predict reduced positional errors.


5-(Hydroxymethyl)-2-furfural: a selective inhibitor of DNA polymerase lambda and terminal deoxynucleotidyltransferase.
5-(Hydroxymethyl)-2-furfural (HMF), a pyrolysate of carbohydrate isolated from instant coffee (Coffea arabica L.), selectively inhibits the activities of mammalian DNA polymerase lambda (pol lambda) and terminal deoxynucleotidyltransferase (TdT) which are family X pols, in vitro. The compound influenced neither the activities of replicative DNA polymerases such as alpha, delta, and epsilon, nor even the activity of pol beta which is from the same family and thought to have a very similar three-dimensional structure to the pol beta-like region of pol lambda. Since parts of HMF such as furan, furfuryl alcohol, and 2-furaldehyde did not influence the activities of any enzymes tested, the substituted form of furan with a hyroxymethyl group and a formyl group might be important for the inhibition of pol lambda and TdT. The inhibitory effect of HMF on intact pol lambda (i.e., residues 1-575), a truncated pol lambda lacking the N-terminal BRCA1 C-terminus domain (133-575, del-1 pol lambda) and another truncated pol lambda lacking the N-terminal proline-rich region (245-575, del-2 pol lambda) was dose-dependent, and 50% inhibition was observed at a concentration of 26.1, 10.3, and 4.6 microM, respectively. The IC(50) value of HMF for TdT was the same as that for del-2 pol lambda (5.5 microM). The HMF-induced inhibition of both pol lambda and TdT activities was competitive with respect to both the DNA template-primer and the dNTP substrate. On the basis of these results, HMF was suggested to bind to the pol beta-like region of pol lambda and TdT.


A new cone-beam computed tomography dosimetry method providing optimal measurement positions: A Monte Carlo study.
The conventional weighted computed tomography dose index (CTDIw) may not be suitable for cone-beam computed tomography (CBCT) dosimetry because a cross-sectional dose distribution is angularly inhomogeneous owing to partial angle irradiations. This study was conducted to develop a new dose metric (f(0)CBw) for CBCT dosimetry to determine a more accurate average dose in the central cross-sectional plane of a cylindrical phantom using Monte Carlo simulations. First, cross-sectional dose distributions of cylindrical polymethyl methacrylate phantoms over a wide range of phantom diameters (8-40 cm) were calculated for various CBCT scan protocols. Then, by obtaining linear least-squares fits of the full datasets of the cross-sectional dose distributions, the optimal radial positions, which represented measurement positions for the average phantom dose, were determined. Finally, the f(0)CBw method was developed by averaging point doses at the optimal radial positions of the phantoms. To demonstrate its validity, the relative differences between the average doses and each dose index value were estimated for the devised f(0)CBw, conventional CTDIw, and Haba's CTDIw methods, respectively. The relative differences between the average doses and each dose index value were within 4.1%, 16.7%, and 11.9% for the devised, conventional CTDIw, and Haba's CTDIw methods, respectively. The devised f(0)CBw value was calculated by averaging four "point doses" at 90° intervals and the optimal radial positions of the cylindrical phantom. The devised method can estimate the average dose more accurately than the previously developed CTDIw methods for CBCT dosimetry.


Oral substitution treatment of injecting opioid users for prevention of HIV infection.
Injecting drug users are vulnerable to infection with Human Immunodeficiency Virus (HIV) and other blood borne viruses as a result of collective use of injecting equipment as well as sexual behaviour To assess the effect of oral substitution treatment for opioid dependent injecting drug users on risk behaviours and rates of HIV infections We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and PsycINFO to May 2011. We also searched reference lists of articles, reviews and conference abstracts Studies were required to consider the incidence of risk behaviours, or the incidence of HIV infection related to substitution treatment of opioid dependence. All types of original studies were considered. Two authors independently assessed each study for inclusion Two authors independently extracted key information from each of the included studies. Any differences were resolved by discussion or by referral to a third author. Thirty-eight studies, involving some 12,400 participants, were included. The majority were descriptive studies, or randomisation processes did not relate to the data extracted, and most studies were judged to be at high risk of bias. Studies consistently show that oral substitution treatment for opioid-dependent injecting drug users with methadone or buprenorphine is associated with statistically significant reductions in illicit opioid use, injecting use and sharing of injecting equipment. It is also associated with reductions in the proportion of injecting drug users reporting multiple sex partners or exchanges of sex for drugs or money, but has little effect on condom use. It appears that the reductions in risk behaviours related to drug use do translate into reductions in cases of HIV infection. However, because of the high risk of bias and variability in several aspects of the studies, combined totals were not calculated. Oral substitution treatment for injecting opioid users reduces drug-related behaviours with a high risk of HIV transmission, but has less effect on sex-related risk behaviours. The lack of data from randomised controlled studies limits the strength of the evidence presented in this review.


Coexistence of neurofibromatosis type 1 with multiple malignant neoplasia.
Neurofibromatosis type 1 (NF1, von Recklinghausen disease) is inherited in autosomal dominant way genetic disorder, with an incidence at birth 1:3000. It is one of the most common congenital disorders. It is characterized by café-au-lait spots, neurofibromas, and less common MPTST and gliomas of the optic nerve. It is caused by germline mutations of the NF1 gene, which acts as tumor suppressor. Inactivation of the gene leads to increased activation of the kinase pathways, and in consequence, uncontrolled proliferation of cells. The disease predisposes to the development of both benign and malignant tumors. Malignant tumors, but not related to the nervous system occur in neurofibromatosis quite rare. The aim of the study is a literature review of NF1, with presentation of a patient with NF1 and coexisting numerous tumors: synchronous somatostatinoma and gastrointestinal stromal tumor with metachronous prostate adenocarcinoma and non-small cell lung carcinoma. And attempt to answer the question if there is a common pathway for oncogenesis of these four tumors.


Insights into Streptococcus agalactiae PI-2b pilus biosynthesis and role in adherence to host cells.
The core PI-2b pilus present in "hypervirulent" ST-17 Streptococcus agalactiae strains consists of three pilin subunits (Spb1, Ap1 and Ap2) assembled by sortase SrtC1 and cell-wall anchored by Srt2. Spb1 was shown to be the major pilin and Ap2 the anchor pilin. Ap1 is a putative adhesin. Two additional genes, orf and lep, are part of this operon. The contribution of Lep and Ap1 to the biogenesis of the PI-2b pilus was investigated. Concerning the role of PI-2b, we found that higher PI-2b expression resulted in higher adherence to human brain endothelial cells and higher phagocytosis by human THP1 macrophages.


The study design elements employed by researchers in preclinical animal experiments from two research domains and implications for automation of systematic reviews.
Systematic reviews are increasingly using data from preclinical animal experiments in evidence networks. Further, there are ever-increasing efforts to automate aspects of the systematic review process. When assessing systematic bias and unit-of-analysis errors in preclinical experiments, it is critical to understand the study design elements employed by investigators. Such information can also inform prioritization of automation efforts that allow the identification of the most common issues. The aim of this study was to identify the design elements used by investigators in preclinical research in order to inform unique aspects of assessment of bias and error in preclinical research. Using 100 preclinical experiments each related to brain trauma and toxicology, we assessed design elements described by the investigators. We evaluated Methods and Materials sections of reports for descriptions of the following design elements: 1) use of comparison group, 2) unit of allocation of the interventions to study units, 3) arrangement of factors, 4) method of factor allocation to study units, 5) concealment of the factors during allocation and outcome assessment, 6) independence of study units, and 7) nature of factors. Many investigators reported using design elements that suggested the potential for unit-of-analysis errors, i.e., descriptions of repeated measurements of the outcome (94/200) and descriptions of potential for pseudo-replication (99/200). Use of complex factor arrangements was common, with 112 experiments using some form of factorial design (complete, incomplete or split-plot-like). In the toxicology dataset, 20 of the 100 experiments appeared to use a split-plot-like design, although no investigators used this term. The common use of repeated measures and factorial designs means understanding bias and error in preclinical experimental design might require greater expertise than simple parallel designs. Similarly, use of complex factor arrangements creates novel challenges for accurate automation of data extraction and bias and error assessment in preclinical experiments.


The role of toll-like receptor variants in acute anterior uveitis.
Acute anterior uveitis (AAU) is the most common form of uveitis; however, while it is presumed to have an immunological basis, the precise underlying etiology remains elusive. Toll-like receptors (TLRs) have a key role in linking innate and adaptive immunity, thereby forming a molecular bridge between microbial triggers and the development of AAU. The purpose of this study was to investigate the role of TLR2 and TLR4 gene polymorphisms in the pathogenesis of AAU. The study comprised 225 confirmed cases of idiopathic or human leukocyte antigen (HLA) B27 (subtypes B*2701-2759; HLA-B27)-related AAU and 2,534 population-based controls from the Blue Mountains Eye Study. All participants were of Anglo-Celtic descent. Blood samples were collected for DNA extraction and genotyping. A total of 16 single nucleotide polymorphisms (SNPs) were selected for analysis and either directly genotyped or imputed to cover the common variations within the TLR genes. Data were analyzed at the allelic, genotypic and haplotypic levels. Control subjects were significantly older than case subjects (p<0.0001). There was no significant difference in the gender composition between the case and control cohorts (p=0.18). One TLR2 SNP (rs11938228) was found to be associated with AAU at the allelic level (OR=1.28; p=0.017); however this association did not remain following adjustment for age and sex (p=0.067). None of the SNPs at the TLR4 locus were found to differ significantly between cases or controls, irrespective of adjustment for age and gender. This study has confirmed that common TLR variants of moderate effect size do not predispose to AAU, undermining the implication of reported mutations in the selective perturbations of TLR expression and function evident in AAU.


The impact of urea on toxic diatoms - Potential effects of fertilizer silo breakdown on a Pseudo-nitzschia bloom.
In spring 2016, two silos containing liquid nitrogen-containing fertilizer collapsed on a harbor in Fredericia, Denmark. More than 2,750 tons of fertilizer spilled into inner Danish waters. A bloom of Pseudo-nitzschia occurred approximately one month after the incident. The bloom caused a 5-week quarantine of numerous mussel-harvesting areas along the eastern coast of Jutland. The levels of domoic acid measured up to 49 mg kg-1 in mussel meat after the bloom. In the months following the event, the species diversity of phytoplankton was low, while the abundance was high comprising few dominant species including Pseudo-nitzschia. The main part of the liquid nitrogen-containing compound was urea, chemically produced for agricultural use. To investigate the potential impact of urea on Pseudo-nitzschia, four strains, including one strain of P. delicatissima, two of P. seriata and one of P. obtusa, were exposed each to three concentrations of urea in a batch culture experiment: 10 μM, 20 μM and 100 μM N urea, and for comparison one concentration of nitrate (10 μM). Nitrate, ammonium, and urea were metabolized at different rates. Pseudo-nitzschia obtusa produced domoic acid and grew best at low urea concentrations. Both P. seriata strains had a positive correlation between urea concentration and growth rate, and the highest growth rate in the nitrate treatment. One strain of P. seriata produced domoic acid peaking at low N loads (10 µM N urea and 10 µM N nitrate). In conclusion, the ability to adapt to the available nitrogen source and retain a high growth rate was exceedingly varying and not only species-specific but also strain specific.


The roughness of the protein energy landscape results in anomalous diffusion of the polypeptide backbone.
Although protein folding is often described by motion on a funnel-shaped overall topology of the energy landscape, the many local interactions that can occur result in considerable landscape roughness which slows folding by increasing internal friction. Recent experimental results have brought to light that this roughness also causes unusual diffusional behaviour of the backbone of an unfolded protein, i.e. the relative motion of protein sections cannot be described by the normal diffusion equation, but shows strongly subdiffusional behaviour with a nonlinear time dependence of the mean square displacement, 〈r(2)(t)〉∝t(α) (α≪ 1). This results in significantly slower configurational equilibration than had been assumed hitherto. Analysis of the results also allows quantification of the energy landscape roughness, i.e. the root-mean-squared depth of local minima, yielding a value of 4-5kBT for a typical small protein.


Effect of low-level laser therapy on wound healing and patients' response after scalpel gingivectomy: A randomized clinical split-mouth study.
Low-level laser therapy (LLLT) is based on the principle of biostimulation or biomodulation effect. LLLT after gingivectomy has resulted in better wound healing because of its action on collagen synthesis, angiogenesis, and growth factor release. The aim of this split-mouth controlled clinical trial was to assess the effect of LLLT, using diode laser (InGaAsP), on wound healing and patients' response after scalpel gingivectomy. Forty patients with gingival enlargement in the maxillary and mandibular anterior region (bilaterally symmetrical) were included in the study. After gingivectomy, a diode laser (InGaAsP) was randomly applied to one side of the surgical area on the 1st, 3rd, and 7th day postoperatively. The surgical areas were disclosed by a solution (Alpha Plac®) to visualize the areas where the epithelium was absent. Comparison of the surface areas on the LLLT-applied sites and controls was made clinically by visualizing the stained area by two examiners. LLLT-applied sites had significantly lower stained areas signifying improved wound healing compared with the controls on the postoperative 7th and 30th day. Within the limitations of this study, the results indicated that LLLT might improve wound healing after gingivectomy.


Optic Nerve Regeneration After Crush Remodels the Injury Site: Molecular Insights From Imaging Mass Spectrometry.
Mammalian central nervous system axons fail to regenerate after injury. Contributing factors include limited intrinsic growth capacity and an inhibitory glial environment. Inflammation-induced optic nerve regeneration (IIR) is thought to boost retinal ganglion cell (RGC) intrinsic growth capacity through progrowth gene expression, but effects on the inhibitory glial environment of the optic nerve are unexplored. To investigate progrowth molecular changes associated with reactive gliosis during IIR, we developed an imaging mass spectrometry (IMS)-based approach that identifies discriminant molecular signals in and around optic nerve crush (ONC) sites. ONC was performed in rats, and IIR was established by intravitreal injection of a yeast cell wall preparation. Optic nerves were collected at various postcrush intervals, and longitudinal sections were analyzed with matrix-assisted laser desorption/ionization (MALDI) IMS and data mining. Immunohistochemistry and confocal microscopy were used to compare discriminant molecular features with cellular features of reactive gliosis. IIR increased the area of the crush site that was occupied by a dense cellular infiltrate and mass spectral features consistent with lysosome-specific lipids. IIR also increased immunohistochemical labeling for microglia and macrophages. IIR enhanced clearance of lipid sulfatide myelin-associated inhibitors of axon growth and accumulation of simple GM3 gangliosides in a spatial distribution consistent with degradation of plasma membrane from degenerated axons. IIR promotes a robust phagocytic response that improves clearance of myelin and axon debris. This growth-permissive molecular remodeling of the crush injury site extends our current understanding of IIR to include mechanisms extrinsic to the RGC.


Peptidomic analysis of cartilage and subchondral bone in OA patients.
The objective of this study was to develop a method for directly analysing osteochondral samples straight out of the operating room without cell culturing, thereby enabling identification of potential peptide biomarkers to better understand the mechanisms involved in the development of osteoarthritis and pain. Osteochondral plugs from wounded and macroscopically nonwounded zones of the femur condyle were collected from six patients with manifest osteoarthritis (OA) undergoing total knee arthroplasty (TKA). The samples were demineralized and supernatant was collected and isotopically marked with Tandem Mass Tag (TMT) labelling and analysed using liquid chromatography coupled with tandem mass spectrometry LC-MS/MS. Using peptidomics, 6292 endogenous peptides were identified. Five hundred sixty-six peptides (8 identified endogenous peptides) differed significantly (P-value 0.10) from wounded zones compared to nonwounded zones. This pilot study shows promising results for enabling peptidomic analysis of cartilage and bone straight out of the operating room. With further refinement, peptidomics can potentially become a diagnostic tool for OA, and improve the knowledge of disease progression and genesis of pain.


Pulsed resource availability changes dietary niche breadth and partitioning between generalist rodent consumers.
Identifying the mechanisms that structure niche breadth and overlap between species is important for determining how species interact and assessing their functional role in an ecosystem. Without manipulative experiments, assessing the role of foraging ecology and interspecific competition in structuring diet is challenging. Systems with regular pulses of resources act as a natural experiment to investigate the factors that influence the dietary niches of consumers. We used natural pulses of mast-fruiting of American beech (Fagus grandifolia) to test whether optimal foraging or competition structure the dietary niche breadth and overlap between two congener rodent species (Peromyscus leucopus and P. maniculatus), both of which are generalist consumers. We reconstructed diets seasonally over a 2-year period using stable isotope analysis (δ13C, δ15N) of hair and of potential dietary items and measured niche dynamics using standard ellipse area calculated within a Bayesian framework. Changes in niche breadth were generally consistent with predictions of optimal foraging theory, with both species consuming more beechnuts (a high-quality food resource) and having a narrower niche breadth during masting seasons compared to nonmasting seasons when dietary niches expanded and more fungi (a low-quality food source) were consumed. In contrast, changes in dietary niche overlap were consistent with competition theory, with higher diet overlap during masting seasons than during nonmasting seasons. Overall, dietary niche dynamics were closely tied to beech masting, underscoring that food availability influences competition. Diet plasticity and niche partitioning between the two Peromyscus species may reflect differences in foraging strategies, thereby reducing competition when food availability is low. Such dietary shifts may have important implications for changes in ecosystem function, including the dispersal of fungal spores.


Attenuation of High-Fat Diet-Induced Rat Liver Oxidative Stress and Steatosis by Combined Hydroxytyrosol- (HT-) Eicosapentaenoic Acid Supplementation Mainly Relies on HT.
Pharmacological therapy for nonalcoholic fatty liver disease (NAFLD) is not approved at the present time. For this purpose, the effect of combined eicosapentaenoic acid (EPA; 50 mg/kg/day) modulating hepatic lipid metabolism and hydroxytyrosol (HT; 5 mg/kg/day) exerting antioxidant actions was evaluated on hepatic steatosis and oxidative stress induced by a high-fat diet (HFD; 60% fat, 20% protein, and 20% carbohydrates) compared to a control diet (CD; 10% fat, 20% protein, and 70% carbohydrates) in mice fed for 12 weeks. HFD-induced liver steatosis (i) was reduced by 32% by EPA, without changes in oxidative stress-related parameters and mild recovery of Nrf2 functioning affording antioxidation and (ii) was decreased by 42% by HT, concomitantly with total regain of the glutathione status diminished by HFD, 42% to 59% recovery of lipid peroxidation and protein oxidation enhanced by HFD, and regain of Nrf2 functioning, whereas (iii) combined EPA + HT supplementation elicited 74% reduction in liver steatosis, with total recovery of the antioxidant potential in a similar manner than HT. It is concluded that combined HT + EPA drastically decreases NAFLD development, an effect that shows additivity in HT and EPA effects that mainly relies on HT, strengthening the impact of oxidative stress as a central mechanism underlying liver steatosis in obesity.


Extending systematic reviews to include evidence on implementation: methodological work on a review of community-based initiatives to prevent injuries.
Unintentional injury is a leading cause of mortality and disability among young and old. While evidence about the effectiveness of interventions in reducing injuries is accumulating, reviews of this evidence frequently fail to include details of implementation processes. Our research, of which the work reported here formed a part, had two main objectives: (1) to identify evidence about the implementation of interventions aimed at reducing unintentional injuries amongst children and young people; and (2) to explore methods for systematically reviewing evidence on implementation. Existing systematic reviews of the effectiveness of interventions aiming to reduce unintentional injuries in children and young people formed the starting point for the work reported here. In summary, many of the published papers we identified contained little information on implementation processes and, even when these were discussed, the extent to which authors' claims were based on research evidence was unclear. On the basis of the studies we reviewed implementation data were insufficiently strong to provide a sound evidence base for practitioners and policymakers. Notwithstanding this, we identified valuable data about the context in which such initiatives are implemented and the type of factors that might impinge on implementation. This work has implications in three areas: (1) researchers with an interest in evidence-based public health could be encouraged to consider implementation issues in the design of intervention studies; (2) funding bodies could be encouraged to prioritise intervention studies using mixed methods that will enable researchers to consider effectiveness and implementation; (3) journal editors could work towards increasing the quality of reporting on implementation issues through the development of guidelines.


Recent advances in the management of obstructive sleep apnea: The dental perspective.
Obstructive sleep apnea (OSA) is common in adult population. OSA shows detrimental effects on health, neuropsychological development, quality-of-life, and economic potential and now it is recognized as a public health problem. Despite the availability of expanded therapeutic options, polysomnography and nasal continuous positive airway pressure (CPAP) are the gold standards for the diagnosis and treatment for OSA. Recently, American Academy of Sleep Medicine has recommended oral appliances for OSA. Hence the therapeutic interventions that are directed at the site of airway obstruction in the maxillofacial region are within the scope of dentistry. Treatment of OSA can improve vitality, social and daytime functioning, family life and mental health of a person and hence the quality-of-life. Obesity is the main predisposing factor for OSA. Other than obesity, craniofacial abnormalities such as micrognathia and retrognathia, age, ethnic background and genetic predisposition, consumption of alcohol, smoking, and sedatives may also predispose to OSA. Treatment modalities for OSA are behavior modification, diet and medication, CPAP devices, surgical (maxillo-mandibular advancement surgery), and oral appliances. Treatment of a patient with OSA not only improves the physical health of the patients but also the mental and social well-being.