Idiopathic Fistula in an Unrepaired Submucous Cleft Palate.

Palatal fistulae are a recognised complication in individuals who have undergone surgical repair of a cleft palate, however, congenital or idiopathic palatal fistulae are rare. This report discusses the presentation and treatment of a 16-year-old female with a submucous cleft palate, who presented with a recent onset change in speech and evidence of a new palatal fistula. There was no history of recent infection or known trauma, and the patient had not undergone any previous palatal surgery. This report discusses the clinical presentation, recommended management and relevant literature for this rare phenomenon.

The Cleft Lip Education with Augmented Reality (CLEAR) VR Phase 2 Trial: A Pilot Randomized Crossover Trial of a Novel Patient Information Leaflet.

BACKGROUND: The Cleft Lip Education with Augmented Reality (CLEAR) project centers around the use of augmented reality (AR) in patient leaflets, as a visual means to overcome the "health literacy" gap. This trial followed Virtual Reality (VR CORE) guidelines for VR Phase 2 (Pilot) trials. METHODS: Participants included families of children treated for Cleft Lip and Palate at the Royal Hospital for Children, Glasgow. Interventions were AR leaflet or Traditional Leaflet. Objectives were to calculate sample sizes, assess outcome instruments, trial design, and acceptability to patients. Primary outcome measure was Mental Effort Rating Scale, and secondary outcomes were Patient Satisfaction (Visual Analogue Scale), Usefulness Scale for Patient Information Material (USE) scale, and Instructional Materials Motivation Survey (IMMS). Randomization was by block randomization. The trial was single blinded with assessors blinded to group assignment. RESULTS: 12 Participants were randomized, with crossover design permitting analysis of 12 per group. Primary outcome with Mental Effort Rating Scale indicated higher mental effort with Traditional compared to AR Leaflet (4.75 vs 2.00, P = .0003). Secondary outcomes for Satisfaction were Traditional 54.50 versus AR 93.50 (P = .0001); USE scale 49.42 versus 74.08 (P = .0011); and IMMS 112.50 versus 161.75 (P = .0003). Subjective interviews noted overwhelmingly positive patient comments regarding the AR leaflet. Outcome instruments and trial design were acceptable to participants. No harms were recorded. CONCLUSIONS: The CLEAR pilot trial provides early evidence of clinical efficacy of AR leaflets in patient education. It is hoped that this will provide a future paradigm shift in the way patient education is delivered.

Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5-MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance. Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5-MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and well-tolerated therapeutic strategy. Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.

The Simons Observatory: metamaterial microwave absorber and its cryogenic applications.

Controlling stray light at millimeter wavelengths requires special optical design and selection of absorptive materials that should be compatible with cryogenic operating environments. While a wide selection of absorptive materials exists, these typically exhibit high indices of refraction and reflect/scatter a significant fraction of light before absorption. For many lower index materials such as commercial microwave absorbers, their applications in cryogenic environments are challenging. In this paper, we present a new tool to control stray light: metamaterial microwave absorber tiles. These tiles comprise an outer metamaterial layer that approximates a lossy gradient index anti-reflection coating. They are fabricated via injection molding commercially available carbon-loaded polyurethane (25% by mass). The injection molding technology enables mass production at low cost. The design of these tiles is presented, along with thermal tests to 1 K. Room temperature optical measurements verify their control of reflectance to less than 1% up to 65∘ angles of incidence, and control of wide angle scattering below 0.01%. The dielectric properties of the bulk carbon-loaded material used in the tiles is also measured at different temperatures, confirming that the material maintains similar dielectric properties down to 3 K.

The Simons Observatory: modeling optical systematics in the Large Aperture Telescope.

We present geometrical and physical optics simulation results for the Simons Observatory Large Aperture Telescope. This work was developed as part of the general design process for the telescope, allowing us to evaluate the impact of various design choices on performance metrics and potential systematic effects. The primary goal of the simulations was to evaluate the final design of the reflectors and the cold optics that are now being built. We describe nonsequential ray tracing used to inform the design of the cold optics, including absorbers internal to each optics tube. We discuss ray tracing simulations of the telescope structure that allow us to determine geometries that minimize detector loading and mitigate spurious near-field effects that have not been resolved by the internal baffling. We also describe physical optics simulations, performed over a range of frequencies and field locations, that produce estimates of monochromatic far-field beam patterns, which in turn are used to gauge general optical performance. Finally, we describe simulations that shed light on beam sidelobes from panel gap diffraction.

Secondary Alveolar Bone Grafting (CLEFTSiS) 2007-2010.

Objective To determine whether alveolar bone graft outcomes for unilateral and bilateral cleft lip and palate patients have continued to improve since the reorganization of cleft services in Scotland in 2000. Design Retrospective analysis of postoperative anterior occlusal radiographs. Patients and Participants Eighty-one of 106 patients who were eligible for alveolar bone grafting between 2007 and 2010 had suitable postoperative radiographs available. Interventions Twenty-seven percent of the patients (n = 22) had presurgical orthodontic intervention. All patients underwent alveolar bone grafting with bone harvested from the iliac crest. Main Outcome Measures The Kindelan bone-fill index was used to evaluate success. Weighted kappa statistics were used to assess intra- and interobserver reproducibility. A comparison was made with results from 2000 to 2004 to assess any improvement. Chi-square tests (or Fisher exact test) were used to determine whether outcomes differed depending on the laterality of the cleft, use of presurgical expansion, or age at bone grafting. Results Interobserver scoring agreement was good (weighted kappa = .383). Intraobserver reproducibility was greater (weighted kappas of .835 and .620). Success was achieved in 99% of bone grafts, compared with 76% in the period from 2000 to 2004 (P < .001). There was no statistically significant relationship between the laterality of the cleft (P = 1.000), use of presurgical expansion (P = 1.000), or age at time of bone grafting and outcome (P = .259). Conclusion Scottish secondary alveolar bone graft outcomes improved during 2007 to 2010 in comparison to the 2000 to 2004 results.

Secondary Alveolar Bone Grafting (CLEFTSiS) 2007-2010.

Objective : To determine whether alveolar bone graft outcomes for unilateral and bilateral cleft lip and palate patients have continued to improve since the reorganization of cleft services in Scotland in 2000. Design : Retrospective analysis of postoperative anterior occlusal radiographs. Patients and Participants : Eighty-one of 106 patients who were eligible for alveolar bone grafting between 2007 and 2010 had suitable postoperative radiographs available. Interventions : Twenty-seven percent of the patients (n = 22) had presurgical orthodontic intervention. All patients underwent alveolar bone grafting with bone harvested from the iliac crest. Main Outcome Measures : The Kindelan bone-fill index was used to evaluate success. Weighted kappa statistics were used to assess intra- and interobserver reproducibility. A comparison was made with results from 2000 to 2004 to assess any improvement. Chi-square tests (or Fisher exact test) were used to determine whether outcomes differed depending on the laterality of the cleft, use of presurgical expansion, or age at bone grafting. Results : Interobserver scoring agreement was good (weighted kappa = .383). Intraobserver reproducibility was greater (weighted kappas of .835 and .620). Success was achieved in 99% of bone grafts, compared with 76% in the period from 2000 to 2004 (P < .001). There was no statistically significant relationship between the laterality of the cleft (P = 1.000), use of presurgical expansion (P = 1.000), or age at time of bone grafting and outcome (P = .259). Conclusion : Scottish secondary alveolar bone graft outcomes improved during 2007 to 2010 in comparison to the 2000 to 2004 results.

Evidence of lensing of the cosmic microwave background by dark matter halos.

We present evidence of the gravitational lensing of the cosmic microwave background by 10(13) solar mass dark matter halos. Lensing convergence maps from the Atacama Cosmology Telescope Polarimeter (ACTPol) are stacked at the positions of around 12 000 optically selected CMASS galaxies from the SDSS-III/BOSS survey. The mean lensing signal is consistent with simulated dark matter halo profiles and is favored over a null signal at 3.2σ significance. This result demonstrates the potential of microwave background lensing to probe the dark matter distribution in galaxy group and galaxy cluster halos.

Over half of the far-infrared background light comes from galaxies at z >or= 1.2.

Submillimetre surveys during the past decade have discovered a population of luminous, high-redshift, dusty starburst galaxies. In the redshift range 1 or= 1.2 accounting for 70% of it. As expected, at the longest wavelengths the signal is dominated by ultraluminous galaxies at z > 1.

Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer.

KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer. Transcriptional and epigenetic profiling studies show reduced RNA Pol II binding and downregulation of genes involved in estrogen signaling, cell cycle, Myc and stem cell pathways associated with CTx-648 anti-tumor activity in ER-positive (ER+) breast cancer. CTx-648 treatment leads to potent tumor growth inhibition in ER+ breast cancer in vivo models, including models refractory to endocrine therapy, highlighting the potential for targeting KAT6A in ER+ breast cancer.

Evidence of galaxy cluster motions with the kinematic Sunyaev-Zel'dovich effect.

Using high-resolution microwave sky maps made by the Atacama Cosmology Telescope, we for the first time present strong evidence for motions of galaxy clusters and groups via microwave background temperature distortions due to the kinematic Sunyaev-Zel'dovich effect. Galaxy clusters are identified by their constituent luminous galaxies observed by the Baryon Oscillation Spectroscopic Survey, part of the Sloan Digital Sky Survey III. We measure the mean pairwise momentum of clusters, with a probability of the signal being due to random errors of 0.002, and the signal is consistent with the growth of cosmic structure in the standard model of cosmology.

Cleft lip and palate in Scotland: a survey.

The aim of the survey was to assess midwives' experiences and knowledge of cleft lip and/or palate (CL+/-P), confidence in supporting the families and giving feeding advice, and to identify areas for input from the cleft team. In order to do so, questionnaires were sent to maternity units across Scotland. The results were as follows: 206 questionnaires were returned (42 per cent response rate). Forty one per cent of the midwives had helped a baby with CL+/-P to be born; 23 per cent knew the incidence of CL+/-P; 33 per cent were aware of the stages in treating CL+/- P; 99 per cent were aware that feeding difficulties are a potential complication. When asked about offering support to the families, 70 per cent were not confident and 60 per cent were not confident at giving feeding advice. Regarding cleft team input, 65 per cent would like a training day, 45 per cent requested small group teaching, 50 per cent would like a website and 57 per cent would like printed literature. Our recommendations are to implement training, for midwives, along with supporting websites and literature.

Five-year prospective fistula audit in a single center. TIG training negates consultant learning curve, but surgeons should beware the mid-range palatal defect.

The aim of primary palatoplasty is to achieve optimum speech with minimal morbidity. Symptomatic fistulae are well-recognised complications of palatoplasty and may require additional surgical intervention, increasing the burden of care. Our aims were to better understand fistula experience in our unit and compare fistula rates between an established consultant and a newly appointed training interface group (TIG) trained consultant. Post-operative fistulae were prospectively and independently recorded by Cleft Clinical Nurse Specialists as part of routine 6-week post-operative reviews. Cleft type and intra-operative hard-soft palate junction (HSPJ) width were prospectively recorded by operating surgeons. Data were collated and analysed using Microsoft Excel. Between 1 January 2014 and 31 December 2018, 250 primary palatoplasties were performed. The overall fistula rate was 8% (0% SMCP, ICP 7%, UCLP 8%, BCLP 22%). Fistulae clustered in clefts with a mid-range HSPJ width of 12-16 mm. Numerically, fistula rates remained similar over time despite increased unit activity (doubling of primary surgeries in 2017 and 2018). There was no significant difference in fistulae rates between surgeons (P > 0.05). Overall fistulae rate compared favourably with published data. TIG fellowships were designed in the context of cleft surgery to address issues relating to steep operative learning curves. These data demonstrate that results from a newly appointed TIG-trained surgeon are comparable to that of an established TIG-trained surgeon. Data also suggest surgeons should be aware of the risk of fistulae in the mid-range palatal defect and in HSPJ widths of 12-16 mm.

The Simons Observatory: A large-diameter truss for a refracting telescope cooled to 1 K.

We present the design and measured performance of a new carbon fiber strut design that is used in a cryogenically cooled truss for the Simons Observatory small aperture telescope. The truss consists of two aluminum 6061 rings separated by 24 struts. Each strut consists of a central carbon fiber tube fitted with two aluminum end caps. We tested the performance of the strut and truss by (i) cryogenically cycling and destructively pull-testing strut samples, (ii) non-destructively pull-testing the final truss, and (iii) measuring the thermal conductivity of the carbon fiber tubes. We found that the strut strength is limited by the mounting fasteners and the strut end caps, not the epoxy adhesive or the carbon fiber tube. This result is consistent with our numerical predictions. Our thermal measurements suggest that the conductive heat load through the struts (from 4 to 1 K) will be less than 1 mW. This strut design may be a promising candidate for use in other cryogenic support structures.

Detection of the power spectrum of cosmic microwave background lensing by the Atacama Cosmology Telescope.

We report the first detection of the gravitational lensing of the cosmic microwave background through a measurement of the four-point correlation function in the temperature maps made by the Atacama Cosmology Telescope. We verify our detection by calculating the levels of potential contaminants and performing a number of null tests. The resulting convergence power spectrum at 2° angular scales measures the amplitude of matter density fluctuations on comoving length scales of around 100 Mpc at redshifts around 0.5 to 3. The measured amplitude of the signal agrees with Lambda cold dark matter cosmology predictions. Since the amplitude of the convergence power spectrum scales as the square of the amplitude of the density fluctuations, the 4σ detection of the lensing signal measures the amplitude of density fluctuations to 12%.

Evidence for dark energy from the cosmic microwave background alone using the Atacama Cosmology Telescope lensing measurements.

For the first time, measurements of the cosmic microwave background radiation (CMB) alone favor cosmologies with w = -1 dark energy over models without dark energy at a 3.2-sigma level. We demonstrate this by combining the CMB lensing deflection power spectrum from the Atacama Cosmology Telescope with temperature and polarization power spectra from the Wilkinson Microwave Anisotropy Probe. The lensing data break the geometric degeneracy of different cosmological models with similar CMB temperature power spectra. Our CMB-only measurement of the dark energy density Ω(Λ) confirms other measurements from supernovae, galaxy clusters, and baryon acoustic oscillations, and demonstrates the power of CMB lensing as a new cosmological tool.

Cleft lip/palate: incidence of prenatal diagnosis in Glasgow, Scotland, and comparison with other centers in the United Kingdom.

OBJECTIVES: To determine the proportion of children with cleft lip and/or cleft palate diagnosed prenatally between 1999 and 2008 in those referred for treatment to the Royal Hospital for Sick Children in Glasgow, Scotland (RHSC); and to compare the percentage prenatally diagnosed in 2008 versus other cleft treatment centers in the U.K. METHOD: A retrospective study was performed using medical records of the 459 cleft patients born and referred to RHSC between 1999 and 2008. Comparable data for year 2008 were requested from other U.K. units. RESULTS: For the period studied, the percentage of all clefts diagnosed prenatally was 15%. This rose to 28% when only the cases of cleft lip with or without cleft palate (CL ± P) were considered. An increase was seen in prenatal detection of CL ± P from 11% in 1999 to 50% in 2008 (p = .011). Two of the six U.K. units that responded had a significantly higher percentage of CL ± P cases diagnosed prenatally compared with RHSC in 2008 (p < .05). CONCLUSIONS: The percentage of CL ± P cases diagnosed prenatally in this study is consistent with the literature and increased between 1999 and 2008. Routine ultrasound anomaly scanning is shown to significantly improve detection rates compared with scanning of high-risk pregnancies only. Cases of CL ± P where the alveolus or the palate is involved have significantly higher detection rates than those involving only the lip.

Preclinical small molecule WEHI-7326 overcomes drug resistance and elicits response in patient-derived xenograft models of human treatment-refractory tumors.

Targeting cell division by chemotherapy is a highly effective strategy to treat a wide range of cancers. However, there are limitations of many standard-of-care chemotherapies: undesirable drug toxicity, side-effects, resistance and high cost. New small molecules which kill a wide range of cancer subtypes, with good therapeutic window in vivo, have the potential to complement the current arsenal of anti-cancer agents and deliver improved safety profiles for cancer patients. We describe results with a new anti-cancer small molecule, WEHI-7326, which causes cell cycle arrest in G2/M, cell death in vitro, and displays efficacious anti-tumor activity in vivo. WEHI-7326 induces cell death in a broad range of cancer cell lines, including taxane-resistant cells, and inhibits growth of human colon, brain, lung, prostate and breast tumors in mice xenografts. Importantly, the compound elicits tumor responses as a single agent in patient-derived xenografts of clinically aggressive, treatment-refractory neuroblastoma, breast, lung and ovarian cancer. In combination with standard-of-care, WEHI-7326 induces a remarkable complete response in a mouse model of high-risk neuroblastoma. WEHI-7326 is mechanistically distinct from known microtubule-targeting agents and blocks cells early in mitosis to inhibit cell division, ultimately leading to apoptotic cell death. The compound is simple to produce and possesses favorable pharmacokinetic and toxicity profiles in rodents. It represents a novel class of anti-cancer therapeutics with excellent potential for further development due to the ease of synthesis, simple formulation, moderate side effects and potent in vivo activity. WEHI-7326 has the potential to complement current frontline anti-cancer drugs and to overcome drug resistance in a wide range of cancers.

The scar on the face of Scotland: deprivation and alcohol-related facial injuries in Scotland.

BACKGROUND: : Recent media and political attention have focused on a "rising tide" of youth violence and alcohol-related problems in Scotland. Facial injuries in Scotland are most commonly sustained as a result of interpersonal violence, and young men are a high risk group for facial injuries. Facial injuries are known to be associated with alcohol consumption but the sociodemographic determinants are not fully known. METHODS: : Influences on the incidence of alcohol-related facial injuries were investigated using data on 22,417 patients between 2001 and 2006 from the Scottish Morbidity Records. RESULTS: : Since 2001, the incidence of alcohol-related facial injuries in Scotland has declined, but the nature and scale of the problem remain considerable, with the major burden for such injuries disproportionately affecting young men from socioeconomically deprived areas. CONCLUSIONS: : The role of poverty as the major determinant of alcohol-related facial injuries has thus far not been explicitly acknowledged. Interventions to change behavior alone are unlikely to succeed unless they are supported by measures designed to improve socioeconomic circumstances and to reduce socioeconomic inequalities.