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Background: To evaluate efficacy, safety, and tolerability of ubrogepant, an oral CGRP receptor antagonist, for acute treatment of a single migraine attack. Methods: Multicenter, randomized, double-blind, placebo-controlled, parallel-group, single-attack, phase 3 study (NCT02828020). Patients randomized 1:1:1 to placebo, ubrogepant 50mg, or ubrogepant 100mg had 60 days to treat one migraine attack (moderate/severe pain intensity). Co-primary efficacy endpoints: pain freedom 2 hours post initial dose and absence of most bothersome migraine-associated symptom (MBS). Results: 1672 patients were randomized (safety population: n=1436; mITT population: n=1327). Mean age: 40.7 years; white (82.4%); female (87.5%). A significantly greater percentage of ubrogepant- than placebo-treated patients achieved pain freedom 2 hours post initial dose (50mg: 19.2%, adjusted P=0.0023; 100mg: 21.2%, adjusted P=0.0003; placebo: 11.8%). A significantly greater percentage of ubrogepant patients achieved absence of MBS (50mg: 38.6%, adjusted P=0.0023, 100mg: 37.7%, adjusted P=0.0023; placebo: 27.8%). The adverse event (AE) profile of ubrogepant was similar to placebo. The most common AEs (incidence ≥2% in any treatment group) within 48 hours of initial or optional second dose were nausea, somnolence, and dry mouth (all with incidence <5%). Conclusions: Both co-primary endpoints were met, with clinically meaningful effects on migraine headache pain and MBS. Ubrogepant was well tolerated, with no identified safety concerns.
Background: To evaluate efficacy, safety, and tolerability of ubrogepant for acute treatment of migraine attacks. Methods: Multicenter, double-blind, phase 3 study (NCT02867709). Randomized patients (1:1:1, placebo or ubrogepant 25mg or 50mg) had 60 days to treat one migraine attack (moderate/severe pain intensity). Co-primary efficacy endpoints (2 hours post initial dose): headache pain freedom and absence of most bothersome migraine-associated symptom (MBS). Secondary endpoints: pain relief, sustained pain relief, sustained pain freedom, and absence of migraine-associated symptoms. Results: 1686 patients were randomized (safety population: n=1465; mITT population: n=1355). Mean age: 41 years; white: 81%; female: 89%. Significantly greater proportions of ubrogepant- than placebo-treated patients achieved 2-hour pain freedom (placebo: 14.3%; 25mg: 20.7%, adjusted P=0.0285; 50mg: 21.8%, adjusted P=0.0129) and absence of MBS for 50mg (placebo: 27.4%; 50mg: 38.9%, adjusted P=0.0129). Secondary endpoints (except absence of nausea at 2h) met statistical significance versus placebo for ubrogepant 50mg. Absence of MBS and secondary outcomes were not significant for 25mg after multiplicity adjustment. Ubrogepant’s and placebo’s AE profiles were similar. Conclusions: Co-primary endpoints were met for ubrogepant 50mg. Ubrogepant 25mg was significantly superior to placebo for 2h pain freedom. Ubrogepant was well tolerated. Results support the efficacy, tolerability, and safety of ubrogepant for acute treatment of migraine attacks.
To compare the epidemiologic features (e.g. settings and transmission mode) and patient clinical characteristics associated with outbreaks of different norovirus (Nov) strains, we retrospectively analysed data of Nov outbreaks occurring in Guangzhou, China from 2012 to 2018. The results suggested that outbreaks of Nov GII.2, GII.17 and GII.4 Sydney exhibited different outbreak settings, transmission modes and symptoms. GII.2 outbreaks mainly occurred in kindergartens, elementary and high schools and were transmitted mainly through person-to-person contact. By contrast, GII.4 Sydney outbreaks frequently occurred in colleges and were primarily associated with foodborne transmission. Cases from GII.2 and GII.17 outbreaks reported vomiting more frequently than those from outbreaks associated with GII.4 Sydney.
A viscous damping model is proposed based on a simplified equation of fluid motion in a moonpool or the narrow gap formed by two fixed boxes. The model takes into account the damping induced by both flow separation and wall friction through two damping coefficients, namely, the local and friction loss coefficients. The local loss coefficient is determined through specifically designed physical model tests in this work, and the friction loss coefficient is estimated through an empirical formula found in the literature. The viscous damping model is implemented in the dynamic free-surface boundary condition in the gap of a modified potential flow model. The modified potential flow model is then applied to simulate the wave-induced fluid responses in a narrow gap formed by two fixed boxes and in a moonpool for which experimental data are available. The modified potential flow model with the proposed viscous damping model works well in capturing both the resonant amplitude and frequency under a wide range of damping conditions.
Patient memory for treatment contents is defined as memory for the ideas, concepts, skills, and/or insights (termed treatment points) that the therapist thinks are important for the patient to remember and implement as a part of therapy. This article reviews key findings on patient memory for treatment contents, describes the development and evaluation of the Memory Support Intervention (MSI), and outlines future directions for research. Patient memory for treatment contents is poor, and worse memory is associated with worse treatment outcome. The MSI is composed of eight memory support strategies that therapists incorporate frequently alongside treatment points delivered during treatment-as-usual. Training therapists to deliver the MSI may yield better treatment outcomes by enhancing patient memory for treatment contents. Future research is needed to understand how to best measure patient memory for treatment contents, and the mediators, moderators, and dissemination potential of the MSI.
Dietary supplementation with the organic chromium (Cr) has been shown to positively affect the immune function of poultry. However, to our knowledge, no experiment has been done to directly compare the impacts of Cr chloride and chromium picolinate (CrPic) on the immune responses of broilers vaccinated with Avian Influenza (AI) virus vaccine. Therefore, the present experiment was conducted to investigate the effects of supplemental Cr sources (Cr chloride and CrPic) and levels on the growth performance and immune responses of broilers vaccinated with AI virus vaccine so as to provide an effective nutritional strategy for improving immune function of broilers. A total of 432 1-day (d)-old male broiler chicks were used in a 1 plus 2×4 design. Chickens were given either a diet without Cr supplementation (control) or diets supplemented with 0.4, 0.8, 1.6, or 3.2 mg Cr/kg as either Cr chloride or CrPic for 42 d. Compared to the control, dietary Cr supplementation had no effect (P>0.05) on average daily gain, average daily feed intake and gain : feed of broilers during the starter and grower phases, but increased (P<0.05) the relative weights of bursa of fabricius on d 21 and thymus, spleen, or bursa of fabricius on d 42, serum antibody titers against AI virus on d 21, 28, 35 and 42, blood T-lymphocyte transformation rate on d 28 and 42, blood T-lymphocyte percentage on d 42, and serum interleukin-2 contents on d 28. Broilers fed the diets supplemented with the inorganic Cr chloride had higher (P<0.05) weights of thymus, spleen and bursa of fabricius than those fed the diets supplemented with the CrPic on d 42. In addition, broilers fed the diets supplemented with the CrPic had higher (P<0.05) antibody titers against AI virus than those fed the diets supplemented with the inorganic Cr chloride on d 21 and 35. These results indicate that dietary Cr supplementation improved immune responses of broilers vaccinated with AI virus, and the inorganic Cr chloride was more effective than the CrPic in increasing the relative weights of lymphoid organs, however, the CrPic was more effective than the inorganic Cr chloride in enhancing the serum antibody titer against AI virus.
Focused electron beam-induced deposition (FEBID) is capable of producing metal-containing nanostructures with lateral resolution on the sub-nanometer scale. Practical application of this nanofabrication technique has been hindered by ligand-derived contamination from precursors developed for thermal deposition methods. Mechanistic insight into FEBID through surface science studies and gas-phase electron–molecule interactions has begun to enable the design of custom FEBID precursors. These studies have shown that precursors designed to decompose under electron irradiation can produce high-purity FEBID deposits. Herein, we highlight the progress in FEBID precursor development with several examples that incorporate this mechanism-based design approach.
Litter size has a great impact on the profit of swine producers. Uterine development is an important determinant of reproduction efficiency and could hence affect litter size. Chinese Erhualian pig is one of the most prolific breeds in the world, even though large phenotypic variation in litter size was observed within Erhualian sows. To dissect the genetic basis of the phenotypic variation, we herein conducted genome-wide association studies for total number born and number born alive (NBA) of Erhualian sows. In total, one significant single nucleotide polymorphism (SNP) (P<1.78e−06) and 11 suggestive SNPs (P<3.57e−05) were identified on 10 chromosomes, confirming seven previously reported quantitative trait loci (QTL) and uncovering six QTL for litter size or uterus length. One locus on Sus scrofa chromosome (SSC) 13 (79.28 to 90.43 Mb) harbored a cluster of suggestive SNPs associated with multiparous NBA. The SNP (rs81447100) within this region was confirmed to be significantly (P<0.05) associated with litter size in Erhualian (n=313), Sutai (n=173) and Yorkshire (n=488) populations. Retinol binding protein 2 and retinol binding protein 1 functionally related to the development of uterus were located in a region of 2 Mb around rs81447100. Moreover, four genes related to embryo implantation and development were also detected around other significant SNPs. Taken together, our findings provide a potential marker (rs81447100) for the genetic improvement of litter size not only in Chinese Erhualian pigs but also in European commercial pig breeds like Yorkshire, and would facilitate the final identification of causative variant(s) underlying the effect of SSC13 QTL on litter size.
We report our investigations on the host galaxy properties of stellar binary black holes (SBBHs) by implementing simple recipes for SBBH formation and merger into cosmological galaxy formation model. If the time delay between SBBH formation and merger ranges from Gyr to the Hubble time, SBBH mergers at redshift z < 0.3 occur preferentially in big galaxies with stellar mass M* > 2 × 1010M⊙ and metallicities Z peaking around ~0.6Z⊙. However, the host galaxy stellar mass distribution of heavy SBBH mergers (with total black hole mass >50M⊙) is bimodal with one peak at ~109M⊙ and the other peak at ~2 × 1010M⊙. The contribution fraction from metal-poor host galaxies (Z < 0.2Z⊙) to heavy mergers is much larger than that to less heavy mergers. If SBBHs were formed in the early universe, their mergers detected at z < 0.3 occur preferentially in even more massive galaxies with M* > 3 × 1010M⊙ and in galaxies with metallicities mostly >0.2Z⊙ and peaking at Z ~ 0.6Z⊙.
Family history is a long-standing and readily obtainable risk factor for schizophrenia (SCZ). Low-cost genotyping technologies have enabled large genetic studies of SCZ, and the results suggest the utility of genetic risk scores (GRS, direct assessments of inherited common variant risk). Few studies have evaluated family history and GRS simultaneously to ask whether one can explain away the other.
We studied 5959 SCZ cases and 8717 controls from four Nordic countries. All subjects had family history data from national registers and genome-wide genotypes that were processed through the quality control procedures used by the Psychiatric Genomics Consortium. Using external training data, GRS were estimated for SCZ, bipolar disorder (BIP), major depression, autism, educational attainment, and body mass index. Multivariable modeling was used to estimate effect sizes.
Using harmonized genomic and national register data from Denmark, Estonia, Norway, and Sweden, we confirmed that family history of SCZ and GRS for SCZ and BIP were risk factors for SCZ. In a joint model, the effects of GRS for SCZ and BIP were essentially unchanged, and the effect of family history was attenuated but remained significant. The predictive capacity of a model including GRS and family history neared the minimum for clinical utility.
Combining national register data with measured genetic risk factors represents an important investigative approach for psychotic disorders. Our findings suggest the potential clinical utility of combining GRS and family history for early prediction and diagnostic improvements.
Vortex-induced vibration (VIV) is an important physical phenomenon as one design a riser or a cylindrical structure in ocean. As the riser or the cylindrical structure is adjacent to a seabed, the boundary effect on VIV is not fully understood yet. The direct-forcing immersed boundary (DFIB) method is used to investigate a two-degree-of-freedom VIV of a flexible supported circular cylinder adjacent to a plane boundary in this study. Furthermore, the effect of the VIV of cylinder on skin friction of the plane boundary is investigated. The effects of varying reduced velocity and gap ratio on VIV are discussed. Only a single vortex street is found when the cylinder is close to plane boundary. Hydrodynamic coefficients of the freely vibrating cylinder are analyzed in time and spectral domains. Furthermore, nearly round oval-shaped motion is observed as the so-called lock-in phenomenon occurs. The skin friction of the plane boundary is predicted by the DFIB model. Results show that the vibrating cylinder in the boundary layer flow can reduce the friction effectively. This proposed DFIB model can be useful for the investigation of VIV of the structures under the plane boundary effect even for a small gap between the cylinder and the boundary.
Ocular toxoplasmosis (OT) caused by Toxoplasma gondii is a major cause of infectious uveitis, however little is known about its immunopathological mechanism. Susceptible C57BL/6 (B6) and resistant BALB/c mice were intravitreally infected with 500 tachyzoites of the RH strain of T. gondii. B6 mice showed more severe ocular pathology and higher parasite loads in the eyes. The levels of galectin (Gal)-9 and its receptors (Tim-3 and CD137), interferon (IFN)-γ, IL-6 and IL-10 were significantly higher in the eyes of B6 mice than those of BALB/c mice; however, the levels of IFN-α and -β were significantly decreased in the eyes and CLNs of B6 mice but significantly increased in BALB/c mice after infection. After blockage of galectin–receptor interactions by α-lactose, neither ocular immunopathology nor parasite loads were different from those of infected BALB/c mice without α-lactose treatment. Although the expressions of Gal-9/receptor were significantly increased in B6 mice and Gal-1 and -3 were upregulated in both strains of mice upon ocular T. gondii infection, blockage of galectins did not change the ocular pathogenesis of genetic resistant BALB/c mice. However, IFN-α and -β were differently expressed in B6 and BALB/c mice, suggesting that type I IFNs may play a protective role in experimental OT.
Rice planthopper (RPH) populations of Nilaparvata lugens and Sogatella furcifera periodically have erupted across Asia. Predicting RPH population dynamics and identifying their source areas are crucial for the management of these migratory pests in China, but the origins of the migrants to temperate and subtropical regions in China remains unclear. In particular, their early migration to China in March and April have not yet been explored due to a lack of research data available from potential source areas, Central Vietnam and Laos. In this study, we examined the population dynamics and migratory paths of N. lugens and S. furcifera in Vietnam and South China in 2012 and 2013. Trajectory modeling showed that in March and April in 2012 and 2013, RPH emigrated from source areas in Central Vietnam where rice was maturing to the Red River Delta and South China. Early migrants originated from Southern Central Vietnam (14–16°N), but later most were from Northern Central Vietnam (16–19°N). Analysis of meteorological and light-trap data from Hepu in April (1977–2013) using generalized linear models showed that immigration increased with precipitation in Southern Central Vietnam in January, but declined with precipitation in Northern Central Vietnam in January. These results determined that the RPH originate from overwintering areas in Central Vietnam, but not from southernmost areas of Vietnam. Winter precipitation, rather than temperature was the most important factor determining the number of RPH migrants. Based on their similar population dynamics and low population densities in Central Vietnam, we further speculated that RPH migrate to track ephemeral food resources whilst simultaneously avoiding predators. Migrations do not seem to be initiated by interspecific competition, overcrowding or host deterioration. Nevertheless, S. furcifera establishes populations earlier than N. lugens South China, perhaps to compensate for interspecific competition. We provide new information that could assist with forecasting outbreaks and implementing control measures against these migratory pests.
Dengue fever (DF) is the most prevalent and rapidly spreading mosquito-borne disease globally. Control of DF is limited by barriers to vector control and integrated management approaches. This study aimed to explore the potential risk factors for autochthonous DF transmission and to estimate the threshold effects of high-order interactions among risk factors. A time-series regression tree model was applied to estimate the hierarchical relationship between reported autochthonous DF cases and the potential risk factors including the timeliness of DF surveillance systems (median time interval between symptom onset date and diagnosis date, MTIOD), mosquito density, imported cases and meteorological factors in Zhongshan, China from 2001 to 2013. We found that MTIOD was the most influential factor in autochthonous DF transmission. Monthly autochthonous DF incidence rate increased by 36·02-fold [relative risk (RR) 36·02, 95% confidence interval (CI) 25·26–46·78, compared to the average DF incidence rate during the study period] when the 2-month lagged moving average of MTIOD was >4·15 days and the 3-month lagged moving average of the mean Breteau Index (BI) was ⩾16·57. If the 2-month lagged moving average MTIOD was between 1·11 and 4·15 days and the monthly maximum diurnal temperature range at a lag of 1 month was <9·6 °C, the monthly mean autochthonous DF incidence rate increased by 14·67-fold (RR 14·67, 95% CI 8·84–20·51, compared to the average DF incidence rate during the study period). This study demonstrates that the timeliness of DF surveillance systems, mosquito density and diurnal temperature range play critical roles in the autochthonous DF transmission in Zhongshan. Better assessment and prediction of the risk of DF transmission is beneficial for establishing scientific strategies for DF early warning surveillance and control.