Dominant Mutations in GRHL3 Cause Van der Woude Syndrome and Disrupt Oral Periderm Development

Mutations in interferon regulatory factor 6 (IRF6) account for ∼70% of cases of Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate. In 8 of 45 VWS-affected families lacking a mutation in IRF6, we found coding mutations in grainyhead-like 3 (GRHL3). According to a zebrafish-based assay, the disease-associated GRHL3 mutations abrogated periderm development and were consistent with a dominant-negative effect, in contrast to haploinsufficiency seen in most VWS cases caused by IRF6 mutations. In mouse, all embryos lacking Grhl3 exhibited abnormal oral periderm and 17% developed a cleft palate. Analysis of the oral phenotype of double heterozygote (Irf6+/−;Grhl3+/−) murine embryos failed to detect epistasis between the two genes, suggesting that they function in separate but convergent pathways during palatogenesis. Taken together, our data demonstrated that mutations in two genes, IRF6 and GRHL3, can lead to nearly identical phenotypes of orofacial cleft. They supported the hypotheses that both genes are essential for the presence of a functional oral periderm and that failure of this process contributes to VWS

Near-Ultraviolet Properties of a Large Sample of Type Ia Supernovae as Observed with the Swift UVOT

We present ultraviolet (UV) and optical photometry of 26 Type Ia supernovae (SNe~Ia) observed from March 2005 to March 2008 with the NASA {\it Swift} Ultraviolet and Optical Telescope (UVOT). The dataset consists of 2133 individual observations, making it by far the most complete study of the UV emission from SNe~Ia to date. Grouping the SNe into three subclasses as derived from optical observations, we investigate the evolution of the colors of these SNe, finding a high degree of homogeneity within the normal subclass, but dramatic differences between that group and the subluminous and SN 2002cx-like groups. For the normal events, the redder UV filters on UVOT ($u$, $uvw1$) show more homogeneity than do the bluer UV filters ($uvm2$, $uvw2$). Searching for purely UV characteristics to determine existing optically based groupings, we find the peak width to be a poor discriminant, but we do see a variation in the time delay between peak emission and the late, flat phase of the light curves. The UV light curves peak a few days before the $B$ band for most subclasses (as was previously reported by Jha et al. 2006a), although the SN 2002cx-like objects peak at a very early epoch in the UV. That group also features the bluest emission observed among SNe~Ia. As the observational campaign is ongoing, we discuss the critical times to observe, as determined by this study, in order to maximize the scientific output of future observations.Comment: Accepted to Astrophysical Journa

Dominant Mutations in GRHL3 Cause Van der Woude Syndrome and Disrupt Oral Periderm Development

Peer reviewe

Catching Element Formation In The Act

Gamma-ray astronomy explores the most energetic photons in nature to address some of the most pressing puzzles in contemporary astrophysics. It encompasses a wide range of objects and phenomena: stars, supernovae, novae, neutron stars, stellar-mass black holes, nucleosynthesis, the interstellar medium, cosmic rays and relativistic-particle acceleration, and the evolution of galaxies. MeV gamma-rays provide a unique probe of nuclear processes in astronomy, directly measuring radioactive decay, nuclear de-excitation, and positron annihilation. The substantial information carried by gamma-ray photons allows us to see deeper into these objects, the bulk of the power is often emitted at gamma-ray energies, and radioactivity provides a natural physical clock that adds unique information. New science will be driven by time-domain population studies at gamma-ray energies. This science is enabled by next-generation gamma-ray instruments with one to two orders of magnitude better sensitivity, larger sky coverage, and faster cadence than all previous gamma-ray instruments. This transformative capability permits: (a) the accurate identification of the gamma-ray emitting objects and correlations with observations taken at other wavelengths and with other messengers; (b) construction of new gamma-ray maps of the Milky Way and other nearby galaxies where extended regions are distinguished from point sources; and (c) considerable serendipitous science of scarce events -- nearby neutron star mergers, for example. Advances in technology push the performance of new gamma-ray instruments to address a wide set of astrophysical questions.Comment: 14 pages including 3 figure

Evidence for Type Ia Supernova Diversity from Ultraviolet Observations with the Hubble Space Telescope

We present ultraviolet (UV) spectroscopy and photometry of four Type Ia supernovae (SNe 2004dt, 2004ef, 2005M, and 2005cf) obtained with the UV prism of the Advanced Camera for Surveys on the Hubble Space Telescope. This dataset provides unique spectral time series down to 2000 Angstrom. Significant diversity is seen in the near maximum-light spectra (~ 2000--3500 Angstrom) for this small sample. The corresponding photometric data, together with archival data from Swift Ultraviolet/Optical Telescope observations, provide further evidence of increased dispersion in the UV emission with respect to the optical. The peak luminosities measured in uvw1/F250W are found to correlate with the B-band light-curve shape parameter dm15(B), but with much larger scatter relative to the correlation in the broad-band B band (e.g., ~0.4 mag versus ~0.2 mag for those with 0.8 < dm15 < 1.7 mag). SN 2004dt is found as an outlier of this correlation (at > 3 sigma), being brighter than normal SNe Ia such as SN 2005cf by ~0.9 mag and ~2.0 mag in the uvw1/F250W and uvm2/F220W filters, respectively. We show that different progenitor metallicity or line-expansion velocities alone cannot explain such a large discrepancy. Viewing-angle effects, such as due to an asymmetric explosion, may have a significant influence on the flux emitted in the UV region. Detailed modeling is needed to disentangle and quantify the above effects.Comment: 17 pages, 13 figures, accepted by Ap

International Olympic Committee consensus statement on pain management in elite athletes

Pain is a common problem among elite athletes and is frequently associated with sport injury. Both pain and injury interfere with the performance of elite athletes. There are currently no evidence-based or consensus-based guidelines for the management of pain in elite athletes. Typically, pain management consists of the provision of analgesics, rest and physical therapy. More appropriately, a treatment strategy should address all contributors to pain including underlying pathophysiology, biomechanical abnormalities and psychosocial issues, and should employ therapies providing optimal benefit and minimal harm. To advance the development of a more standardised, evidence-informed approach to pain management in elite athletes, an IOC Consensus Group critically evaluated the current state of the science and practice of pain management in sport and prepared recommendations for a more unified approach to this important topic

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

A História da Alimentação: balizas historiográficas

Os M. pretenderam traçar um quadro da História da Alimentação, não como um novo ramo epistemológico da disciplina, mas como um campo em desenvolvimento de práticas e atividades especializadas, incluindo pesquisa, formação, publicações, associações, encontros acadêmicos, etc. Um breve relato das condições em que tal campo se assentou faz-se preceder de um panorama dos estudos de alimentação e temas correia tos, em geral, segundo cinco abardagens Ia biológica, a econômica, a social, a cultural e a filosófica!, assim como da identificação das contribuições mais relevantes da Antropologia, Arqueologia, Sociologia e Geografia. A fim de comentar a multiforme e volumosa bibliografia histórica, foi ela organizada segundo critérios morfológicos. A seguir, alguns tópicos importantes mereceram tratamento à parte: a fome, o alimento e o domínio religioso, as descobertas européias e a difusão mundial de alimentos, gosto e gastronomia. O artigo se encerra com um rápido balanço crítico da historiografia brasileira sobre o tema

Global Health and Emergency Care: Defining Clinical Research Priorities

OBJECTIVES: Despite recent strides in the development of global emergency medicine (EM), the field continues to lag in applying a scientific approach to identifying critical knowledge gaps and advancing evidence-based solutions to clinical and public health problems seen in emergency departments (EDs) worldwide. Here, progress on the global EM research agenda created at the 2013 Academic Emergency Medicine Global Health and Emergency Care Consensus Conference is evaluated and critical areas for future development in emergency care research internationally are identified. METHODS: A retrospective review of all studies compiled in the Global Emergency Medicine Literature Review (GEMLR) database from 2013 through 2015 was conducted. Articles were categorized and analyzed using descriptive quantitative measures and structured data matrices. The Global Emergency Medicine Think Tank Clinical Research Working Group at the Society for Academic Emergency Medicine 2016 Annual Meeting then further conceptualized and defined global EM research priorities utilizing consensus-based decision making. RESULTS: Research trends in global EM research published between 2013 and 2015 show a predominance of observational studies relative to interventional or descriptive studies, with the majority of research conducted in the inpatient setting in comparison to the ED or prehospital setting. Studies on communicable diseases and injury were the most prevalent, with a relative dearth of research on chronic noncommunicable diseases. The Global Emergency Medicine Think Tank Clinical Research Working Group identified conceptual frameworks to define high-impact research priorities, including the traditional approach of using global burden of disease to define priorities and the impact of EM on individual clinical care and public health opportunities. EM research is also described through a population lens approach, including gender, pediatrics, and migrant and refugee health. CONCLUSIONS: Despite recent strides in global EM research and a proliferation of scholarly output in the field, further work is required to advocate for and inform research priorities in global EM. The priorities outlined in this paper aim to guide future research in the field, with the goal of advancing the development of EM worldwide