Longitudinal Speech Outcome at 5 and 10 Years in UCLP: Influence of Speech Therapy and Secondary Velopharyngeal Surgery.

OBJECTIVE: To investigate speech development of children aged 5 and 10 years with repaired unilateral cleft lip and palate (UCLP) and identify speech characteristics when speech proficiency is not at 'peer level' at 10 years. Estimate how the number of speech therapy visits are related to speech proficiency at 10 years, and what factors are predictive of whether a child's speech proficiency at 10 years is at 'peer level' or not. DESIGN: Longitudinal complete datasets from the Scandcleft project. PARTICIPANTS: 320 children from nine cleft palate teams in five countries, operated on with one out of four surgical methods. INTERVENTIONS: Secondary velopharyngeal surgery (VP-surgery) and number of speech therapy visits (ST-visits), a proxy for speech intervention. MAIN OUTCOME MEASURES: 'Peer level' of percentage of consonants correct (PCC, > 91%) and the composite score of velopharyngeal competence (VPC-Sum, 0-1). RESULTS: Speech proficiency improved, with only 23% of the participants at 'peer level' at 5 years, compared to 56% at 10 years. A poorer PCC score was the most sensitive marker for the 44% below 'peer level' at 10-year-of-age. The best predictor of 'peer level' speech proficiency at 10 years was speech proficiency at 5 years. A high number of ST-visits received did not improve the probability of achieving 'peer level' speech, and many children seemed to have received excessive amounts of ST-visits without substantial improvement. CONCLUSIONS: It is important to strive for speech at 'peer level' before age 5. Criteria for speech therapy intervention and for methods used needs to be evidence-based.

Muc5b is required for airway defence.

Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC). However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus. Genetic variants are linked to diverse lung diseases, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b(-/-) mice. By contrast, in mice that transgenically overexpress Muc5b, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.

Charge Transfer and Built-in Electric Fields between a Crystalline Oxide and Silicon.

We report charge transfer and built-in electric fields across the epitaxial SrNb_{x}Ti_{1-x}O_{3-δ}/Si(001) interface. Electrical transport measurements indicate the formation of a hole gas in the Si and the presence of built-in fields. Hard x-ray photoelectron measurements reveal pronounced asymmetries in core-level spectra that arise from these built-in fields. Theoretical analysis of core-level spectra enables built-in fields and the resulting band bending to be spatially mapped across the heterojunction. The demonstration of tunable charge transfer, built-in fields, and the spatial mapping of the latter, lays the groundwork for the development of electrically coupled, functional heterojunctions.

First Measurement of Electron Neutrino Appearance in NOvA.

We report results from the first search for ν_{µ}→ν_{e} transitions by the NOvA experiment. In an exposure equivalent to 2.74×10^{20} protons on target in the upgraded NuMI beam at Fermilab, we observe 6 events in the Far Detector, compared to a background expectation of 0.99±0.11(syst) events based on the Near Detector measurement. A secondary analysis observes 11 events with a background of 1.07±0.14(syst). The 3.3σ excess of events observed in the primary analysis disfavors 0.1π<δ_{CP}<0.5π in the inverted mass hierarchy at the 90% C.L.

The association of psychosocial screening and service provision in pediatric oncology: the Psychosocial Assessment Tool (PAT2.0) into clinical practice.

PURPOSE: Distress screening in oncology has been widely endorsed in recent years. However, current knowledge of the impact of screening on delivery of clinical psychosocial services is limited. This study investigated the association between screening and psychosocial services in the early period following diagnosis of childhood cancer. METHODS: The Psychosocial Assessment Tool (PAT2.0) was administered by clinical social workers in two pediatric oncology centers shortly following diagnosis. Psychosocial service activity in the first 8 weeks post diagnosis was collected via social work surveys and extraction of information from hospital databases. RESULTS: PAT2.0 and psychosocial service data were obtained for 89 families with a child newly diagnosed with cancer. Distribution of PAT2.0 risk categories was consistent with previous studies (57.3 % universal, 38.2 % targeted, 4.5 % clinical). Significant, weak to moderate correlations between PAT2.0 and social workers' estimates of psychosocial risk were observed. No significant differences in the amount of psychosocial services provided to families with "universal" versus "elevated" (i.e., targeted or clinical) risk were found. Number of days in hospital was strongly and positively associated with the amount of psychosocial services families received in the first 8 weeks following diagnosis. CONCLUSIONS: Psychosocial risk, as measured by the PAT2.0, and allocation of psychosocial services were not significantly associated in the early period following diagnosis. Further investigation is required to understand if differences emerge over time when psychosocial screening is implemented clinically. Development of clinical pathways of care needs to account for patients who may predominantly be treated in the outpatient setting.

Work-related stress and reward: an Australian study of multidisciplinary pediatric oncology healthcare providers.

OBJECTIVE: Managing staff stress and preventing long-term burnout in oncology staff are highly important for both staff and patient well-being. Research addressing work-related stress in adult oncology is well documented; however, less is known about this topic in the pediatric context. This study examined sources of work-related stress and reward specific to multidisciplinary staff working in pediatric oncology in Australia. METHOD: Participants were 107 pediatric oncology clinicians, including medical, nursing, and allied health staff from two Australian pediatric oncology centers. Participants completed an online survey using two newly developed measures: the work stressors scale-pediatric oncology and the work rewards scale-pediatric oncology. RESULTS: The most commonly reported sources of both stress and reward are related to patient care and interactions with children. Results indicated that levels of work-related stress and reward were similar between the professional disciplines and between the two hospitals. Regression analyses revealed no demographic or organizational factors that were associated with either stress or reward. CONCLUSIONS: Work-related stress and reward are not mutually exclusive; particular situations and events can be simultaneously stressful and rewarding for healthcare providers. Although patient care and interactions with children was found to be the most stressful aspect of working in this speciality, it was also the greatest source of reward. Results are discussed in relation to workplace approaches to staff well-being and stress reduction.

Constitutive production of catalytic antibodies to a Staphylococcus aureus virulence factor and effect of infection.

Antibodies that recognize microbial B lymphocyte superantigenic epitopes are produced constitutively with no requirement for adaptive immune maturation. We report cleavage of the Staphylococcus aureus virulence factor extracellular fibrinogen-binding protein (Efb) by catalytic antibodies produced with no exposure to the bacterium and reduction of the catalytic antibody activity following infection. IgG catalytic antibodies that specifically hydrolyzed Efb via a nucleophilic catalytic mechanism were found in the blood of healthy humans and aseptic mice free of S. aureus infection. IgG hydrolyzed peptide bonds on the C-terminal side of basic amino acids, including a bond located within the C3b-binding domain of Efb. Efb digested with the IgG lost its ability to bind C3b and inhibit complement-dependent antibody-mediated red blood cell lysis. In addition to catalysis, the IgG expressed saturable Efb binding activity. IgG from S. aureus-infected mice displayed reduced Efb cleaving activity and increased Efb binding activity compared with uninfected controls, suggesting differing effects of the infection on the antibody subsets responsible for the two activities. IgG from children hospitalized for S. aureus infection also displayed reduced Efb cleavage compared with healthy children. These data suggest a potential defense function for constitutively produced catalytic antibodies to a putative superantigenic site of Efb, but an adaptive catalytic response appears to be proscribed.

A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus.

Neutrophil extracellular traps (NETs) are webs of DNA covered with antimicrobial molecules that constitute a newly described killing mechanism in innate immune defense. Previous publications reported that NETs take up to 3-4 h to form via an oxidant-dependent event that requires lytic death of neutrophils. In this study, we describe neutrophils responding uniquely to Staphylococcus aureus via a novel process of NET formation that did not require neutrophil lysis or even breach of the plasma membrane. The multilobular nucleus rapidly became rounded and condensed. During this process, we observed the separation of the inner and outer nuclear membranes and budding of vesicles, and the separated membranes and vesicles were filled with nuclear DNA. The vesicles were extruded intact into the extracellular space where they ruptured, and the chromatin was released. This entire process occurred via a unique, very rapid (5-60 min), oxidant-independent mechanism. Mitochondrial DNA constituted very little if any of these NETs. They did have a limited amount of proteolytic activity and were able to kill S. aureus. With time, the nuclear envelope ruptured, and DNA filled the cytoplasm presumably for later lytic NET production, but this was distinct from the vesicular release mechanism. Panton-Valentine leukocidin, autolysin, and a lipase were identified in supernatants with NET-inducing activity, but Panton-Valentine leukocidin was the dominant NET inducer. We describe a new mechanism of NET release that is very rapid and contributes to trapping and killing of S. aureus.

First divertor Thomson scattering measurements on MAST-U.

MAST-U is equipped with a Super-X divertor, which aims to reduce heat flux to the target and promote detachment. Measurements of plasma electron density and temperature in the Super-X chamber offer insight into the processes at work in this type of divertor. First data have been obtained from the MAST-U divertor Thomson scattering diagnostic designed to measure these quantities. Following a Raman scattering calibration in nitrogen, the diagnostic operated over a number of plasma pulses in the first physics campaign. Electron density and temperature measurements have been taken in attached and detached conditions as the strike leg moved through the field of view of the diagnostic. The system operated with a dedicated 30 Hz laser with timing synchronized to seven similar lasers installed in the core Thomson system. Electron densities in the range of 1 × 1018-5 × 1019 m-3 have been measured by the system throughout these regimes. Although the system was specified to measure from 1 to 40 eV, electron temperatures in the Super-X divertor in the first campaign were low, and measurement down to 0.5 eV has been critical, particularly close to the detachment front. This generation of polychromator has been designed with increased stray light rejection compared to those used in the core system. This has proved successful with very low levels of stray light observed.

An evaluation of homesickness in children: A systematic review and meta-analysis.

OBJECTIVE: To provide a systematic review and meta-analysis of the quantitative literature on homesickness in children, including how it is assessed and relationship to other negative states. STUDY SELECTION AND SYNTHESIS: A literature search was conducted using Medline, PsychINFO and Scopus databases. Studies were included if they assessed homesickness in children under eighteen years of age and were published in peer reviewed journals in the English language between 1990 and December 2020. A total of 176 studies were screened for relevance and 17 met the inclusion criteria for the systematic review with five studies included in the meta-analysis. MAIN OUTCOMES AND MEASURES: The primary outcome measure was homesickness severity, and it was examined in relation to measures of depression and anxiety. The literature in relation to known risk and protective factors was also reviewed. RESULTS: Homesickness was reported in the majority of children who were separated from their home. It was associated with negative emotional states. A total of seventeen studies were included in the quantitative review. The meta-analysis showed a significant relationship between homesickness and depression r=0.431 (95% CI 0.344-0.510; p<0.001) and homesickness and anxiety r=0.426 (95% CI 0.369-0.479; p<0.001). Age was not a significant moderator of homesickness severity. Consideration of effective interventions to address homesickness was limited. CONCLUSIONS AND RELEVANCE: Homesickness significantly impacts children's well-being regardless of age and is associated with overall distress, depression and anxiety. Future studies are required to examine homesickness interventions and supports to improve well-being in children.

Low temperature Thomson scattering on MAST-U.

A new divertor Thomson scattering system has been developed for the MAST-U tokamak. The diagnostic will produce electron density and temperature profiles along the Super-X strike leg. The existing polychromator design has been adapted for low temperature measurements. A new 1061 nm channel with 2 nm bandwidth has been added to enable measurements down below the previous ∼5 eV limit on the core system. The optical filters used in the system have OD6 light rejection alongside a 1064.1 nm laser line filter to reduce stray light in the digitized channels. A new averaging technique has been applied to the scattered signal traces to improve the core Thomson data in the scrape-off layer. The technique reduces the systematic noise level in this region. This leads to a reduction in the error values for electron density and temperature measurements and, in particular, the digitizer noise. The technique has been applied to produce a radial profile for a number of L-mode MAST discharges down to very low densities of ∼1 × 1018 m-3.

Comparing cortico-motor hotspot identification methods in the lower extremities post-stroke: MEP amplitude vs. latency.

Transcranial magnetic stimulation (TMS) is a technique used to probe and measure cortico-motor responses of the nervous system. However, lower extremity (LE) specific methodology has been slow to develop. In this retrospective analysis, we investigated what motor evoked potential metric, amplitude (MEPamp) or latency (MEPlat), best distinguished the motor-cortical target, i.e. hotspot, of the tibialis anterior and soleus post-stroke. Twenty-three participants with stroke were included in this investigation. Neuronavigation was used to map hotspots, derived via MEPamp and MEPlat, over a 3cm × 5cm grid. Distances between points with the greatest response within a session and between days were compared. Both criterion, amplitude and latency, provided poor identification of locations between trials within a session, and between multiple visits. Identified hotspots were similar only 15 % and 8% of the time between two assessments within the same session, for amplitude and latency respectively. However, MEPamp was more consistent in identifying hotspots, evidenced by locations being less spatially distant from each other (Amplitude: 1.4 cm (SD 0.10) Latency: 1.7 (SD 1.04), P = 0.008) within a session and between days (Amplitude: 1.3 cm (SD 0.95), Latency 1.9 cm (SD 1.14), P = 0.004). While more work is needed to develop LE specific methodology for TMS, especially as it applies to investigating gait impairments, MEPamp appears to be a more consistent criterion for hotspot identification when compared to MEPlat. It is recommended that future works continue to use MEPamp when identifying tibialis anterior and soleus hotspots using neuronavigation.

A structural model of the Staphylococcus aureus ClfA-fibrinogen interaction opens new avenues for the design of anti-staphylococcal therapeutics.

The fibrinogen (Fg) binding MSCRAMM Clumping factor A (ClfA) from Staphylococcus aureus interacts with the C-terminal region of the fibrinogen (Fg) gamma-chain. ClfA is the major virulence factor responsible for the observed clumping of S. aureus in blood plasma and has been implicated as a virulence factor in a mouse model of septic arthritis and in rabbit and rat models of infective endocarditis. We report here a high-resolution crystal structure of the ClfA ligand binding segment in complex with a synthetic peptide mimicking the binding site in Fg. The residues in Fg required for binding to ClfA are identified from this structure and from complementing biochemical studies. Furthermore, the platelet integrin alpha(IIb)beta(3) and ClfA bind to the same segment in the Fg gamma-chain but the two cellular binding proteins recognize different residues in the common targeted Fg segment. Based on these differences, we have identified peptides that selectively antagonize the ClfA-Fg interaction. The ClfA-Fg binding mechanism is a variant of the "Dock, Lock and Latch" mechanism previously described for the Staphylococcus epidermidis SdrG-Fg interaction. The structural insights gained from analyzing the ClfANFg peptide complex and identifications of peptides that selectively recognize ClfA but not alpha(IIb)beta(3) may allow the design of novel anti-staphylococcal agents. Our results also suggest that different MSCRAMMs with similar structural organization may have originated from a common ancestor but have evolved to accommodate specific ligand structures.

De novo synthesis of alkyne substituted tryptophans as chemical probes for protein profiling studies.

De novo synthesis of alkynalted tryptophan moieties as chemical probes for protein profilling studies, via an unexpected synthesis of Michael acceptor 12 is reported. Friedel Craft's alkylation of 12 and alkyne substituted indoles gave alkynalated tryptophan moieties, which perform as chemical probe by incorporating into actively translating Escherichia coli cells, whereby the alkyne moiety enables multimodal analyses through click chemistry mediated attachment of reporting groups.

Direction-specific interaction forces underlying zinc oxide crystal growth by oriented attachment.

Crystallization by particle attachment is impacting our understanding of natural mineralization processes and holds promise for novel materials design. When particles assemble in crystallographic alignment, expulsion of the intervening solvent and particle coalescence are enabled by near-perfect co-alignment via interparticle forces that remain poorly quantified. Here we report measurement and simulation of these nanoscale aligning forces for the ZnO(0001)-ZnO(000[Formula: see text]) system in aqueous solution. Dynamic force spectroscopy using nanoengineered single crystal probes reveals an attractive force with 60o rotational periodicity. Calculated distance and orientation-dependent potentials of mean force show several attractive free energy wells distinguished by numbers of intervening water layers, which reach a minimum when aligned. The calculated activation energy to separate the attractively bound solvated interfaces perfectly reproduces the measured 60o periodicity, revealing the key role of intervening water structuring as a basis to generate the interparticle torque that completes alignment and enables coalescence.Crystal growth is a fundamental process, important in a wide range of fields, but the interparticle forces responsible for molecule alignment are not well understood. Here, the authors measure the alignment forces in ZnO using dynamic force spectroscopy, highlighting the role of intervening water molecules.

Profiling the tumor microenvironment proteome in prostate cancer using laser capture microdissection coupled to LCâ¿¿MSâ¿¿A technical report.

Laser capture microdissection (LCM) allows microscopic procurement of specific cell types from tissue sections. Here, we present an optimized workflow for coupling LCM to LCâ¿¿MS/MS including: sectioning of tissue, a standard LCM workflow, protein digestion and advanced LCâ¿¿MS/MS. Soluble proteins extracted from benign epithelial cells, their associated stroma, tumor epithelial cells and their associated stromal cells from a single patient tissue sample were digested and profiled using advanced LCâ¿¿MS/MS. The correlation between technical replicates was R2 = 0.99 with a mean % CV of 9.55% ± 8.73. The correlation between sample replicates was R2 = 0.97 with a mean % CV of 13.83% ± 10.17. This represents a robust, systematic approach for profiling of the tumor microenvironment using LCM coupled to label-free LCâ¿¿MS/MS.

Stress analysis of hemispherical ceramic hip prosthesis bearings.

We present design criteria and test data for ceramic hemispherical 'resurfacing' prosthesis bearings that are attached by placement on the conical trunnion of the prosthesis stem. These large diameter bearings will be subjected to higher torques than conventional 28 mm bearings. Prototypes were fabricated and tested. The pattern of failure and subsequent analysis suggests that fracture initiated on the surface of the bore and that this was preceded by the development of large circumferential hoop stresses. Widening the bore will improve stability under torque loads but this may be at the expense of bearing strength. A finite element analysis has shown that the optimum taper bore to bearing diameter ratio is 0.43 and that designs with large taper bore to bearing diameter ratios (over 0.6) should be avoided due to the development of excessively high hoop stresses on the inner bore surface. High meridional tensile stresses can appear where the internal roof surface joins the conical bore surface as the load is removed. A smooth radius between the conical bore and the roof will help to overcome this. Further improvements include a thinner roof that is smoothly arched internally. Thus, the design of the component can be optimised, making it less susceptible to fracture without compromising the stability of the ceramic head on its trunnion.

Impact of an inpatient rehabilitation facility on functional outcome and length of stay of burn survivors.

This study reviewed the use of an inpatient rehabilitation unit for burn survivors. We hypothesized that adult burn patients admitted earlier to inpatient rehabilitation have an equal or better functional outcome than those remaining in acute burn center for rehabilitation care. Functional Independence Measure (FIM) data were prospectively collected on our burn center admissions dating January 2002 to August 2003. National rehabilitation data were acquired from eRehabData and burn literature. A total of 217 adult patients survived until hospital discharge, with 21 (9.7%) discharged to inpatient rehabilitation (REHAB). REHAB had larger burn injuries, more inhalation injuries, higher incidence hand/foot burns, and longer length of stay (LOS). REHAB had lower FIM upon rehabilitation facility admission than national averages but greater FIM improvement during comparable rehabilitation LOS. Although our earlier rehabilitation admission strategy results in more frequent rehabilitation unit referrals, patients had shorter burn center LOS and greater FIM improvement compared with limited national burn patient functional outcome data currently available.