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The spread of the Zika virus (ZIKV) in the Americas led to large outbreaks across the region and most of the Southern hemisphere. Of greatest concern were complications following acute infection during pregnancy. At the beginning of the outbreak, the risk to unborn babies and their clinical presentation was unclear. This report describes the methods and results of the UK surveillance response to assess the risk of ZIKV to children born to returning travellers. Established surveillance systems operating within the UK – the paediatric and obstetric surveillance units for rare diseases, and national laboratory monitoring – enabled rapid assessment of this emerging public health threat. A combined total of 11 women experiencing adverse pregnancy outcomes after possible ZIKV exposure were reported by the three surveillance systems; five miscarriages, two intrauterine deaths and four children with clinical presentations potentially associated with ZIKV infection. Sixteen women were diagnosed with ZIKV during pregnancy in the UK. Amongst the offspring of these women, there was unequivocal laboratory evidence of infection in only one child. In the UK, the number and risk of congenital ZIKV infection for travellers returning from ZIKV-affected countries is very small.
Extra-care housing (ECH) has been hailed as a potential solution to some of the problems associated with traditional forms of social care, since it allows older people to live independently, while also having access to care and support if required. However, little longitudinal research has focused on the experiences of residents living in ECH, particularly in recent years. This paper reports on a longitudinal study of four ECH schemes in the United Kingdom. Older residents living in ECH were interviewed four times over a two-year period to examine how changes in their care needs were encountered and negotiated by care workers, managers and residents themselves. This paper focuses on how residents managed their own changing care needs within the context of ECH. Drawing upon theories of the third and fourth age, the paper makes two arguments. First, that transitions across the boundary between the third and fourth age are not always straightforward or irreversible and, moreover, can sometimes be resisted, planned-for and managed by older people. Second, that operational practices within ECH schemes can function to facilitate or impede residents’ attempts to manage this boundary.
Powerful synergies between phosphonate, zinc oxide, and acrylamido-tert-butyl-sulfonate (ATBS) copolymer chemical additives render superior performance in a high-temperature retarder system for oil well grade Portland cement. The phosphonate retarder and ATBS-based retarders establish a two-tiered strength development where amorphous C-S-H converts to crystalline dicalcium silicate hydrate (C2SH) in the first (low compressive strength) tier prior to the reaction of Portlandite with quartz. The three additive retarder system can be tuned with nanosilica to eliminate the two-tiered strength development effect leading to a smooth transition from the cement in the slurry form directly to its highest compressive strength.
Background: Cervical sponylotic myelopathy (CSM) may present with neck and arm pain. This study investiagtes the change in neck/arm pain post-operatively in CSM. Methods: This ambispective study llocated 402 patients through the Canadian Spine Outcomes and Research Network. Outcome measures were the visual analogue scales for neck and arm pain (VAS-NP and VAS-AP) and the neck disability index (NDI). The thresholds for minimum clinically important differences (MCIDs) for VAS-NP and VAS-AP were determined to be 2.6 and 4.1. Results: VAS-NP improved from mean of 5.6±2.9 to 3.8±2.7 at 12 months (P<0.001). VAS-AP improved from 5.8±2.9 to 3.5±3.0 at 12 months (P<0.001). The MCIDs for VAS-NP and VAS-AP were also reached at 12 months. Based on the NDI, patients were grouped into those with mild pain/no pain (33%) versus moderate/severe pain (67%). At 3 months, a significantly high proportion of patients with moderate/severe pain (45.8%) demonstrated an improvement into mild/no pain, whereas 27.2% with mild/no pain demonstrated worsening into moderate/severe pain (P <0.001). At 12 months, 17.4% with mild/no pain experienced worsening of their NDI (P<0.001). Conclusions: This study suggests that neck and arm pain responds to surgical decompression in patients with CSM and reaches the MCIDs for VAS-AP and VAS-NP at 12 months.
Disease surveillance in wildlife populations presents a logistical challenge, yet is critical in gaining a deeper understanding of the presence and impact of wildlife pathogens. Erinaceus coronavirus (EriCoV), a clade C Betacoronavirus, was first described in Western European hedgehogs (Erinaceus europaeus) in Germany. Here, our objective was to determine whether EriCoV is present, and if it is associated with disease, in Great Britain (GB). An EriCoV-specific BRYT-Green® real-time reverse transcription PCR assay was used to test 351 samples of faeces or distal large intestinal tract contents collected from casualty or dead hedgehogs from a wide area across GB. Viral RNA was detected in 10.8% (38) samples; however, the virus was not detected in any of the 61 samples tested from Scotland. The full genome sequence of the British EriCoV strain was determined using next generation sequencing; it shared 94% identity with a German EriCoV sequence. Multivariate statistical models using hedgehog case history data, faecal specimen descriptions and post-mortem examination findings found no significant associations indicative of disease associated with EriCoV in hedgehogs. These findings indicate that the Western European hedgehog is a reservoir host of EriCoV in the absence of apparent disease.
Recent work has implicated one type of horizontal strabismus (exotropia) as a risk factor for schizophrenia. This new insight raises questions about a potential common developmental origin of the two diseases. Seasonality of births is well established for schizophrenia. Seasonal factors such as light exposure affect eye growth and can cause vision abnormalities, but little is known about seasonality of births in strabismus. We examined birth seasonality in people with horizontal strabismus in a retrospective study in Washoe County, Nevada, and re-examined similar previously obtained data from Osaka, Japan. We then compared seasonal patterns of births between strabismus, refractive error, schizophrenia and congenital toxoplasmosis. Patients with esotropia had a significant seasonality of births, with a deficit in March, then increasing to an excess in September, while patients with exotropia had a distinctly different pattern, with an excess of births in July, gradually decreasing to a deficit in November. These seasonalities were statistically significant with either χ2 or Kolmogorov–Smirnov-type statistics. The birth seasonality of esotropia resembled that for hyperopia, with an increase in amplitude, while the seasonality for myopia involved a phase-shift. There was no correlation between seasonality of births between strabismus and congenital toxoplasmosis. The pattern of an excess of summer births for people with exotropia was remarkably similar to the well-established birth seasonality of one schizophrenia subtype, the deficit syndrome, but not schizophrenia as a whole. This suggests a testable hypothesis: that exotropia may be a risk factor primarily for the deficit type of schizophrenia.
The affect of several aberrations on the figures of merit, FOM, used in the identification analysis of diffraction patterns has been examined by generating simulated diffraction traces with mathematically induced errors. Patterns of mixtures with random 20 shifts, intensity variations, and profile broadening were generated for analysis by MATCHDB, and the behavior of three FOMs during the search step was followed. The results have shown that the angle errors are the most serious in degrading the potential for identification of the phases in the mixtures. Intensity errors cause some degradation on the results. Broadening has little affect when using whole-pattern matching methods.
The availability of automated powder diffractometers, APD, has revolutionized the collection of diffraction data and allowed many improvements in the analysis of these data. The biggest change is the ease of digitizing the diffraction trace rather than preparing it as a strip chart on paper from an analog recorder. When the data are collected properly, the trace is a digitized record of intensity versus 2θ. The trace is an accurate representation of the diffraction pattern containing the sample information along with the spectral and instrument aberrations.
A file of digitized diffraction traces for clay minerals has been developed as a test for the usefulness of such traces in the analysis of clays and clay deposits. The kaolin, smectite, mica clay and chlorite groups are represented by patterns of the most common mineral species in the small crystallite size which is typical of their natural occurrences. Patterns are included for the oriented sample and for glycolated and heated samples when appropriate. This database may form a nucleus for an extensive collection of clay mineral traces in the same manner as the early Powder Diffraction File did for the modern PDE.
The use of whole-pattern matching techniques for phase identification provides increased confidence in the phases determined compared with d-I matching and enhances the potential for determining the existence of phases present in low concentrations. Reference patterns from a database of selected phases were compared with the experimental pattern obtained from an unknown, and the results were ranked using figures-of-merit designed to distinguish the best pattern matches. Several different figures-of-merit have been evaluated, all of which proved successful in recognizing the strongest phase but varied with respect to the other phases.
Low-concentration phases are revealed when the patterns of the more abundant phases are stripped from the experimental trace using the best-fit scaled reference traces. Pattern stripping is improved by pattern shifting and profile shape matching which are provided for in the matching program.
Synchrotron radiation was used to obtain a high-resolution powder diffraction pattern of the high-density form of BeH2, a material whose unit-cell dimensions have not previously been determined. The observed d-spacing values were presented to three different computer indexing programs. All three programs returned as best solution a body-centered orthorhombic unit cell with a = 9.082, b = 4.160, c = 7.707 Å and V = 292 Å3. Interpretation of the three-dimensional Patterson led to 12 BeH2 molecules per unit cell; thus, the theoretical density is 0.755 g/cm3. The molecular structure is based on a network of corner-sharing BeH4 tetrahedra rather than flat, infinite chains with hydrogen bridges previously assumed.
Clay minerals are one of the most difficult classes of materials to analyze by x-ray powder diffraction, yet powder diffraction is the only technique which can yield the important crystallographic information necessary to identify and classify the minerals. The importance of clay minerals in industry and in the studies of rocks, due to their chemical properties and sensitivity to geological changes, often requires the analyses of large numbers of samples in short periods of time. Such sample throughput requires computerized analysis* Because definitive, meaningful d-I data are difficult to obtain from the broad diffraction peaks obtained from most clay samples, this problem has been approached by using the whole diffraction, trace as the basis of a computerized analytical scheme.
Quantitative X-ray powder diffraction using the complete digitized diffraction pattern has proved to be an effective approach to improving the accuracy of the analysis of complex mineral mixtures, provided representative reference patterns and accurate Reference Intensity Ratio (RIR) factors arc available for each component phase. However, chemical and structural variability of common rock-forming minerals may complicate the pattern fitting approach. A method has been developed which utilizes X-ray fluorescence chemistry of an unknown and realistic compositional ranges for component phases as constraints on the quantitative XRD analysis without significant compromise of the pattern fit. This unique approach no only yields accurate weight fractions, but also provides indications of the specific compositions of each phase present in the mixture.
In powder diffraction experiments involving mixtures of compounds, identification of each individual phase is complicated by the presence of other phases. The interpretation of such complex patterns is often very difficult, and much effort has gone into computational search-match algorithms which attempt to identify individual phases (Nichols, 1966; Johnson, 1977; Frevel, 1976). The success achieved by these programs and by manual search-match methods accounts for the fact that X-ray diffractionists have, in the past, not actively searched for other techniques that could be used to simplify such complex problems. In a recent work (Nichols & Johnson, 1980), a comparison was made of the search-match methodologies employed by several similar technologies (mass spectroscopy, fingerprint identification, X-ray diffraction etc.). A significant observation was made that only in the X-ray method was there so much emphasis on analysis of phases in their “as received” condition. In the other cases, emphasis was placed on the separation of phases before obtaining the spectra. A classical example is the GC-MS instrument which employs a gas chromatograph to separate phases before the mass spectrographic analysis is carried out on what are, by that time, essentially pure phases.
An X-ray fluorescence method is presented for the analysis of tungsten-molybdenum solutions. Tungsten and molybdenum metal powders, produced by a fused-salt electrolysis procedure, are dissolved and analyzed for tungsten and molybdenum by using the W La1, Pt La1 intensity ratios. The platinum spectral line from the X-ray tube target serves as a self-internal standard. The sensitivity limit is about 0,05% and in the concentration range of 0.5 to 100%, the accuracy of analysis is within about 2% standard deviation. The technique is also applied to the analysis of tungsten and molybdenum in fused salts and to the determination of several other Impurity elements in these metals.
A double detector modification for the General Electric X-ray unit is described. The detector consists of a double-window flow proportional counter tube backed up by a sealed krypton-filled counter tube. This allows counting of either soft or hard radiation at maximum efficiencies without the necessity of changing counter tubes. Advantages in specific applications are discussed.
Digenetic trematodes of the genus Clinostomum are cosmopolitan parasites infecting fishes, amphibians, reptiles, and snails as intermediate hosts. Despite the broad geographical distribution of this genus, debate about the number of species and how they vary in host use has persisted. To better understand patterns of infection among host species and across life stages, we used large-scale field surveys and molecular tools to examine five species of amphibians and seven species of fishes from 125 California ponds. Among the 12,360 examined hosts, infection was rare, with an overall prevalence of 1.7% in amphibians and 9.2% in fishes. Molecular evidence indicated that both groups were infected with Clinostomum marginatum. Using generalized linear mixed effects models, host species identity and host life stage had a strong influence on infection status, such that Lepomis cyanellus (green sunfish) (49.3%) and Taricha granulosa (rough skinned newt) (9.2%) supported the highest overall prevalence values, whereas adult amphibians tended to have a higher prevalence of infection relative to juveniles (13.3% and 2.5%, respectively). Experimentally, we tested the susceptibility of two amphibian hosts (Pseudacris regilla [Pacific chorus frog] and Anaxyrus boreas [western toad]) to varying levels of cercariae exposure and measured metacercariae growth over time. Pseudacris regilla was 1.3× more susceptible to infection, while infection success increased with cercariae exposure dose for both species. On average, metacarcariae size increased by 650% over 20 days. Our study highlights the importance of integrating field surveys, genetic tools, and experimental approaches to better understand the ecology of host–parasite interactions.
Studies examining associations between fetal serotonin reuptake inhibitor (SRI) exposure and child autism spectrum disorder (ASD) diagnoses or delayed language remain mixed and rarely prospectively follow children or employ gold-standard assessments. We prospectively followed a cohort of mother–child dyads from pregnancy through early elementary school (N = 178), and obtained maternal and alternate–caregiver ratings of behaviors related to ASD (N = 137), as well as direct, gold-standard assessments of child ASD symptoms and pragmatic language among dyads who experienced prenatal depression and either took SRIs or were medication free during pregnancy (N = 44). Prenatal SRI exposure was related to maternal ratings of ASD-related behaviors (β = 0.24 95% confidence interval; CI [0.07, 0.48]), and, among boys, alternative caregiver ratings (males-only β = 0.28 95% CI [0.02, 0.55], females-only β = −0.21 95% CI [–0.63, 0.08]). However, results of our direct assessments suggest an association between SRI exposure and reduced pragmatic language scores (β = –0.27, 95% CI [–0.53, –0.01], but not ASD (Autism Diagnostic Observation Schedule β = 0.14 95% CI [–0.15, 0.41]; Social Responsiveness Scale β = 0.08 95% CI [–0.25, 0.40]). These discrepancies point to issues regarding how ASD is assessed, and the possibility that SRIs may be more strongly associated with language or other broader behaviors that coincide with ASD. Larger prospective studies that incorporate thorough, gold-standard assessments of ASD, language, and other ASD-related behaviors are needed.
Although stimulants are commonly used for attention-deficit/hyperactivity disorder (ADHD), 10–30% of patients have an inadequate response, adverse events, or comorbidities preventing use. Thus, there is a need for safe, effective nonstimulant options. Extended-release viloxazine (SPN-812), a nonstimulant, is currently in development for the treatment of ADHD in children and adolescents. SPN-812 is a structurally distinct, bicyclic norepinephrine reuptake inhibitor with selective serotonergic activity. Results of the Phase 2 program demonstrated efficacy (improved mean ADHD Rating Scale-IV total score) and safety of SPN-812 in children (6–12 years), as well as an onset of action within 1–2 weeks.
Four ongoing Phase 3 randomized, double-blind, placebo-controlled, outpatient, US studies are investigating the efficacy and safety of once-daily SPN-812 for ADHD in children (ages 6–11; 100–400mg) and adolescents (ages 12–17; 200–600mg). Two studies are enrolling children and two are enrolling adolescents. Eligible subjects are required to have minimum baseline scores of ≥28 for ADHD-RS-5 and ≥4 for Clinical Global Impression-Severity scale (CGI-S). These studies will randomize ∼1200 subjects, with ∼800 subjects receiving SPN-812 over a 1–3-week titration and 5-week maintenance period. The primary endpoint in all studies is mean change from baseline to end of study (EOS) in ADHD-RS-5 total score for SPN-812 vs. placebo. Secondary endpoints include change from baseline to EOS in 30% responder rate (% change: ADHD RS 5); Hyperactivity/Impulsivity and Inattention ADHD-RS-5 subscale scores; Conners 3 Rating Scale (parent and self-report); CGI-S/CGI-I (Improvement); Weiss Functional Impairment Rating Scale (parent report); Parenting Stress Index (children); and Stress Index for Parents of Adolescents (adolescents) after 6–8 weeks of treatment. Safety is assessed via adverse events, clinical laboratory tests, vital signs, electrocardiograms, physical examinations, and the Columbia-Suicide Severity Rating Scale. Phase 3 completers are offered the option of enrolling in an open-label extension study (OLE; up to 3 years) with a starting dose of 100/200mg (children/adolescents). Data will be summarized with descriptive statistics and analyzed using appropriate statistical methods.
As of August 2018, enrollment in 1 child study is complete, and the other 3 trials are at ∼89%; rollover into the OLE is ∼90%.
There is an unmet need for nonstimulant ADHD treatment for children and adolescents that is effective, long-acting, and well tolerated. SPN-812 is being investigated in four Phase 3 randomized, placebo-controlled studies for the treatment of children and adolescents with ADHD, based on demonstrated efficacy and safety in the Phase 2 program.
This study is an encore of a poster presentation at the 2018 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP).
Funding Acknowledgements: Supernus Pharmaceuticals, Inc.