The statement that folate supraphysiological levels in uremic patients do not cause harm should not go unchallenged

Diversity within the major histocompatibility complex (MHC) reflects the immunological fitness of a population. MHC-linked microsatellite markers provide a simple and inexpensive method for studying MHC diversity in large scale studies. We have developed six MHC-linked microsatellite markers in the domestic cat and used these, in conjunction with five neutral microsatellites, to assess MHC diversity in domestic mixed breed (n = 129) and purebred Burmese (n = 61) cat populations in Australia. The MHC of outbred Australian cats is polymorphic (average allelic richness = 8.52) while the Burmese population has much significantly lower MHC diversity (average allelic richness = 6.81; P<0.01). The MHC-linked microsatellites along with MHC cloning and sequencing demonstrated moderate MHC diversity in cheetahs (n = 13) and extremely low diversity in Gir lions (n = 13). Our MHC-linked microsatellite markers have potential future use in diversity and disease studies in other populations and breeds of cats as well as in wild felid species

Within-Compound Versus Public Latrine Access and Child Feces Disposal Practices in Low-Income Neighborhoods of Accra, Ghana.

In crowded urban settlements in low-income countries, many households rely on shared sanitation facilities. Shared facilities are not currently considered "improved sanitation" because of concerns about whether hygiene conditions sufficiently protect users from the feces of others. Prevention of fecal exposure at a latrine is only one aspect of sanitary safety. Ensuring consistent use of latrines for feces disposal, especially child feces, is required to reduce fecal contamination in households and communities. Household crowding and shared latrine access are correlated in these settings, rendering latrine use by neighbors sharing communal living areas as critically important for protecting one's own household. This study in Accra, Ghana, found that household access to a within-compound basic latrine was associated with higher latrine use by children of ages 5-12 years and for disposal of feces of children < 5 years, compared with households using public latrines. However, within-compound access was not associated with improved child feces disposal by other caregivers in the compound. Feces was rarely observed in household compounds but was observed more often in compounds with latrines versus compounds relying on public latrines. Escherichia coli and human adenovirus were detected frequently on household surfaces, but concentrations did not differ when compared by latrine access or usage practices. The differences in latrine use for households sharing within-compound versus public latrines in Accra suggest that disaggregated shared sanitation categories may be useful in monitoring global progress in sanitation coverage. However, compound access did not completely ensure that households were protected from feces and microbial contamination

Using Real-World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic-Pharmacodynamic Study.

Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real-world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first-line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti-drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one-compartment model. A maximum effect (Emax ) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half-maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring "dashboard" to individualize dosing and improve treatment outcomes

In one’s own time: Contesting the temporality and linearity of bereavement

This article explores the experience and meaning of time from the perspective of caregivers who have recently been bereaved following the death of a family member. The study is situated within the broader cultural tendency to understand bereavement within the logic of stages, including the perception of bereavement as a somewhat predictable and certainly time-delimited ascent from a nadir in death to a ‘new normal’ once loss is accepted. Drawing on qualitative data from interviews with 15 bereaved family caregivers we challenge bereavement as a linear, temporally bound process, examining the multiple ways bereavement is experienced and how it variously resists ideas about the timeliness, desirability and even possibility of ‘recovery’. We posit, on the basis of these accounts, that the lived experience of bereavement offers considerable challenges to normative understandings of the social ties between the living and the dead and requires a broader reconceptualization of bereavement as an enduring affective state

The growth of northeastern Tibet and its relevance to large-scale continental geodynamics: A review of recent studies

Recent studies of the northeastern part of the Tibetan Plateau have called attention to two emerging views of how the Tibetan Plateau has grown. First, deformation in northern Tibet began essentially at the time of collision with India, not 10–20 Myr later as might be expected if the locus of activity migrated northward as India penetrated the rest of Eurasia. Thus, the north-south dimensions of the Tibetan Plateau were set mainly by differences in lithospheric strength, with strong lithosphere beneath India and the Tarim and Qaidam basins steadily encroaching on one another as the region between them, the present-day Tibetan Plateau, deformed, and its north-south dimension became narrower. Second, abundant evidence calls for acceleration of deformation, including the formation of new faults, in northeastern Tibet since ~15 Ma and a less precisely dated change in orientation of crustal shortening since ~20 Ma. This reorientation of crustal shortening and roughly concurrent outward growth of high terrain, which swings from NNE-SSW in northern Tibet to more NE-SW and even ENE-WSW in the easternmost part of northeastern Tibet, are likely to be, in part, a consequence of crustal thickening within the high Tibetan Plateau reaching a limit, and the locus of continued shortening then migrating to the northeastern and eastern flanks. These changes in rates and orientation also could result from removal of some or all mantle lithosphere and increased gravitational potential energy per unit area and from a weakening of crustal material so that it could flow in response to pressure gradients set by evolving differences in elevation

Characterizing the Cool KOIs III. KOI-961: A Small Star with Large Proper Motion and Three Small Planets

We present the characterization of the star KOI 961, an M dwarf with transit signals indicative of three short-period exoplanets, originally discovered by the Kepler Mission. We proceed by comparing KOI 961 to Barnard's Star, a nearby, well-characterized mid-M dwarf. By comparing colors, optical and near-infrared spectra, we find remarkable agreement between the two, implying similar effective temperatures and metallicities. Both are metal-poor compared to the Solar neighborhood, have low projected rotational velocity, high absolute radial velocity, large proper motion and no quiescent H-alpha emission--all of which is consistent with being old M dwarfs. We combine empirical measurements of Barnard's Star and expectations from evolutionary isochrones to estimate KOI 961's mass (0.13 +/- 0.05 Msun), radius (0.17 +/- 0.04 Rsun) and luminosity (2.40 x 10^(-3.0 +/- 0.3) Lsun). We calculate KOI 961's distance (38.7 +/- 6.3 pc) and space motions, which, like Barnard's Star, are consistent with a high scale-height population in the Milky Way. We perform an independent multi-transit fit to the public Kepler light curve and significantly revise the transit parameters for the three planets. We calculate the false-positive probability for each planet-candidate, and find a less than 1% chance that any one of the transiting signals is due to a background or hierarchical eclipsing binary, validating the planetary nature of the transits. The best-fitting radii for all three planets are less than 1 Rearth, with KOI 961.03 being Mars-sized (Rp = 0.57 +/- 0.18 Rearth), and they represent some of the smallest exoplanets detected to date.Comment: Accepted to Ap

Prototype Testing Results of Charged Particle Detectors and Critical Subsystems for the ESRA Mission to GTO

The Experiment for Space Radiation Analysis (ESRA) is the latest of a series of Demonstration and Validation (DemVal) missions built by the Los Alamos National Laboratory, with the focus on testing a new generation of plasma and energetic paritcle sensors along with critical subsystems. The primary motivation for the ESRA payloads is to minimize size, weight, power, and cost while still providing necessary mission data. These new instruments will be demonstrated by ESRA through ground-based testing and on-orbit operations to increase their technology readiness level such that they can support the evolution of technology and mission objectives. This project will leverage a commercial off-the-shelf CubeSat avionics bus and commercial satellite ground networks to reduce the cost and timeline associated with traditional DemVal missions. The system will launch as a ride share with the DoD Space Test Program to be inserted in Geosynchronous Transfer Orbit (GTO) and allow observations of the Earth\u27s radiation belts. The ESRA CubeSat consists of two science payloads and several subsystems: the Wide field-of-view Plasma Spectrometer, the Energetic Charged Particle telescope, high voltage power supply, payload processor, flight software architecture, and distributed processor module. The ESRA CubeSat will provide measurements of the plasma and energetic charged particle populations in the GTO environment for ions ranging from ~100 eV to ~1000 MeV and electrons with energy ranging from 100 keV to 20 MeV. ESRA will utilize a commercial 12U bus and demonstrate a low-cost, rapidly deployable spaceflight platform with sufficient SWAP to enable efficient measurements of the charged particle populations in the dynamic radiation belts

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism

ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder