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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.
Two solid state anaerobic digesters (SSADs), 15 L each, were set up for co-digestion of switchgrass with primary digestate of a liquid anaerobic digester (LAD) and the recirculating leachate. Both the LAD and two SSADs were operated at 50°C. The results showed that the bioreactors were not started up stably until day 16 and day 47 for reactors A and B, respectively. The supplement of LAD digestate or injection of sodium hydroxide (NaOH) into the recirculating leachate readily reinitiated the biogas production to normal daily high rates of the two individual SSADs, one on day 16 and the other on day 47. In contrast to reactor A, there was a longer lag phase for bioreactor B, however, it showed 46.2% [77.9 vs 53.3 L kg−1 volatile solid (VS)] more cumulative biogas yields, and higher reduction rate of total solid, VS, cellulose and hemicellulose of 29.5, 31, 40.6 and 15%, respectively, which was likely due to optimized pH and NaOH pretreated switchgrass during start-up period. Methane contents of biogas increased gradually and stabilized at 50% for both reactors, indicating a normal operation of anaerobic digestion lasted for at least 100 days. The determined parameters of digested residues met China organic fertilizer standard (NY 525-2012) except for high moisture and low total nutrient contents. Therefore, the product of SSAD has the potential value of organic fertilizer. It is concluded that the LAD digestate can be reused as inoculums by co-digestion with agricultural residues for biogas and organic fertilizer production in SSAD.
To investigate a Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak event involving multiple healthcare facilities in Riyadh, Saudi Arabia; to characterize transmission; and to explore infection control implications.
Cases presented in 4 healthcare facilities in Riyadh, Saudi Arabia: a tertiary-care hospital, a specialty pulmonary hospital, an outpatient clinic, and an outpatient dialysis unit.
Contact tracing and testing were performed following reports of cases at 2 hospitals. Laboratory results were confirmed by real-time reverse transcription polymerase chain reaction (rRT-PCR) and/or genome sequencing. We assessed exposures and determined seropositivity among available healthcare personnel (HCP) cases and HCP contacts of cases.
In total, 48 cases were identified, involving patients, HCP, and family members across 2 hospitals, an outpatient clinic, and a dialysis clinic. At each hospital, transmission was linked to a unique index case. Moreover, 4 cases were associated with superspreading events (any interaction where a case patient transmitted to ≥5 subsequent case patients). All 4 of these patients were severely ill, were initially not recognized as MERS-CoV cases, and subsequently died. Genomic sequences clustered separately, suggesting 2 distinct outbreaks. Overall, 4 (24%) of 17 HCP cases and 3 (3%) of 114 HCP contacts of cases were seropositive.
We describe 2 distinct healthcare-associated outbreaks, each initiated by a unique index case and characterized by multiple superspreading events. Delays in recognition and in subsequent implementation of control measures contributed to secondary transmission. Prompt contact tracing, repeated testing, HCP furloughing, and implementation of recommended transmission-based precautions for suspected cases ultimately halted transmission.
Much of the interest in youth at clinical high risk (CHR) of psychosis has been in understanding conversion. Recent literature has suggested that less than 25% of those who meet established criteria for being at CHR of psychosis go on to develop a psychotic illness. However, little is known about the outcome of those who do not make the transition to psychosis. The aim of this paper was to examine clinical symptoms and functioning in the second North American Prodrome Longitudinal Study (NAPLS 2) of those individuals whose by the end of 2 years in the study had not developed psychosis.
In NAPLS-2 278 CHR participants completed 2-year follow-ups and had not made the transition to psychosis. At 2-years the sample was divided into three groups – those whose symptoms were in remission, those who were still symptomatic and those whose symptoms had become more severe.
There was no difference between those who remitted early in the study compared with those who remitted at one or 2 years. At 2-years, those in remission had fewer symptoms and improved functioning compared with the two symptomatic groups. However, all three groups had poorer social functioning and cognition than healthy controls.
A detailed examination of the clinical and functional outcomes of those who did not make the transition to psychosis did not contribute to predicting who may make the transition or who may have an earlier remission of attenuated psychotic symptoms.
Dengue is the fastest spreading mosquito-transmitted disease in the world. In China, Guangzhou City is believed to be the most important epicenter of dengue outbreaks although the transmission patterns are still poorly understood. We developed an autoregressive integrated moving average model incorporating external regressors to examine the association between the monthly number of locally acquired dengue infections and imported cases, mosquito densities, temperature and precipitation in Guangzhou. In multivariate analysis, imported cases and minimum temperature (both at lag 0) were both associated with the number of locally acquired infections (P < 0.05). This multivariate model performed best, featuring the lowest fitting root mean squared error (RMSE) (0.7520), AIC (393.7854) and test RMSE (0.6445), as well as the best effect in model validation for testing outbreak with a sensitivity of 1.0000, a specificity of 0.7368 and a consistency rate of 0.7917. Our findings suggest that imported cases and minimum temperature are two key determinants of dengue local transmission in Guangzhou. The modelling method can be used to predict dengue transmission in non-endemic countries and to inform dengue prevention and control strategies.
Multiple human immunodeficiency virus (HIV)-1 genotypes in China were first discovered in Yunnan Province before disseminating throughout the country. As the HIV-1 epidemic continues to expand in Yunnan, genetic characteristics and transmitted drug resistance (TDR) should be further investigated among the recently infected population. Among 2828 HIV-positive samples newly reported in the first quarter of 2014, 347 were identified as recent infections with BED-captured enzyme immunoassay (CEIA). Of them, 291 were successfully genotyped and identified as circulating recombinant form (CRF)08_BC (47.4%), unique recombinant forms (URFs) (18.2%), CRF01_AE (15.8%), CRF07_BC (14.4%), subtype C (2.7%), CRF55_01B (0.7%), subtype B (0.3%) and CRF64_BC (0.3%). CRF08_BC and CRF01_AE were the predominant genotypes among heterosexual and homosexual infections, respectively. CRF08_BC, URFs, CRF01_AE and CRF07_BC expanded with higher prevalence in central and eastern Yunnan. The recent common ancestor of CRF01_AE, CRF07_BC and CRF08_BC dated back to 1983.1, 1992.1 and 1989.5, respectively. The effective population sizes (EPS) for CRF01_AE and CRF07_BC increased exponentially during 1991–1999 and 1994–1999, respectively. The EPS for CRF08_BC underwent two exponential growth phases in 1994–1998 and 2001–2002. Lastly, TDR-associated mutations were identified in 1.8% of individuals. These findings not only enhance our understanding of HIV-1 evolution in Yunnan but also have implications for vaccine design and patient management strategies.
l-Arginine is a nutritionally essential amino acid for spermatogenesis and plays versatile roles in animal health and can be utilized as a potential agent to improve reproductive performance of boars under high ambient temperature. The present study aimed to determine whether dietary l-arginine could alleviate heat stress-induced infertility in boars. In all, 20 boars (PIC 1040; 248.59±3.84 kg BW and 407.65±6.40 days of age) were selected and randomly assigned to four groups (group 0.0%, basal diet; group 0.6%, 0.8% or 1.0%, basal diet added with 0.6%, 0.8% or 1.0% l-arginine (wt:wt), respectively.) The four diets were made isonitrogenous by addition of appropriate amounts of l-alanine. Boars were pre-fed the corresponding experimental diet for 42 days. Then, the semen characteristics and libido were accessed for 6 weeks during the hot summer period (25.5° to 33.0°C). Results show that dietary l-arginine remarkably improved sperm motility, normality, total sperm number and effective total sperm number. Also, dietary l-arginine improved semen antioxidant capacity, such as decrease of malondialdehyde and 8-Hydroxy-2'-deoxyguanosine content in sperm (P<0.05), increase of the ratio of glutathione and oxidized glutathione, total antioxidant capacity, glutathione peroxidase and catalase activities in seminal plasma (P<0.05). Most of mitochondria contained intact ultrastructure in l-arginine-supplemented group which also accompany with higher ATP content than the 0.0% group. The boars fed 0.8% l-arginine show increased levels of estradiol-17β and testosterone and exhibit improved libido performance than boars in the 0.0% group. Adding dietary l-arginine linearly increased (P=0.002) nitric oxide content (as l-arginine increased). The scrotal surface temperature in the 0.6%, 0.8% and 1.0% group were decreased by 0.9°C, 0.9°C and 0.4°C, respectively, compared with the 0.0% group. l-Arginine levels caused linear effect on semen quality and antioxidant capacity, also caused quadratic effect on libido performance. During the hot summer months, the predicted optimal l-arginine levels for best semen quality and antioxidant capacity was 0.8% to 1.0% and for best libido performance was 0.8%. It can be concluded that l-arginine can be used as an effective agent to alleviate heat stress-induced infertility of boar, and that 0.8% to 1.0% can be considered as the optimum dosage.
Fruit flies in the genus Bactrocera are global, economically important pests of agricultural food crops. However, basic life history information about these pests, which is vital for designing more effective control methods, is currently lacking. Artificial diets can be used as a suitable replacement for natural host plants for rearing fruit flies under laboratory conditions, and this study reports on the two-sex life-table parameters of four Bactrocera species (Bactrocera correcta, Bactrocera dorsalis, Bactrocera cucurbitae, and Bactrocera tau) reared on a semi-artificial diet comprising corn flour, banana, sodium benzoate, yeast, sucrose, winding paper, hydrochloric acid and water. The results indicated that the larval development period of B. correcta (6.81 ± 0.65 days) was significantly longer than those of the other species. The fecundity of B. dorsalis (593.60 eggs female−1) was highest among the four species. There were no differences in intrinsic rate of increase (r) and finite rate of increase (λ) among the four species. The gross reproductive rate (GRR) and net reproductive rate (R0) of B. dorsalis were higher than those of the other species, and the mean generation time (T) of B. cucurbitae (42.08 ± 1.21 h) was longer than that of the other species. We conclude that the semi-artificial diet was most suitable for rearing B. dorsalis, due to its shorter development time and higher fecundity. These results will be useful for future studies of fruit fly management.
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.
The autofocusing (AF) performance of cell phone cameras is critically dependent on the design of the voice-coil motor (VCM) used to drive the lens module. Also, the metal springs in the AF module should combine high stiffness with a good actuation response and a light weight. The present study utilizes a reverse engineering approach to construct three-dimensional finite element models of the top and bottom springs in the VCM mechanism. Simulations are then performed to investigate the von Mises stress distribution and stiffness characteristics of the two springs given horizontal and vertical orientations of the AF module, respectively. In performing the simulations, the actuation force is computed using two different analysis methods, namely a simplify structure method and a coupled electromagnetic-structural method. It is shown that the simplify structure method has the advantages of a lower computational complexity and a more comprehensive modeling capability. A further series of simulations is thus to examine the effects of the spring shape parameters on the reaction force developed by the spring stiffness. The results show that the spring stiffness increases with an increasing thickness and a decreasing rib length. The simulation results obtained for different spring shape parameter settings are summarized in the form of a parameter design chart for predicting the reaction force given known values of the spring rib length and spring thickness.
Auditory verbal hallucinations (AVHs) are one of the most common and severe symptoms of schizophrenia, but the neuroanatomical abnormalities underlying AVHs are not well understood. The present study aims to investigate whether AVHs are associated with cortical thinning.
Participants were schizophrenia patients from four centers across China, 115 with AVHs and 93 without AVHs, as well as 261 healthy controls. All received 3 T T1-weighted brain scans, and whole brain vertex-wise cortical thickness was compared across groups. Correlations between AVH severity and cortical thickness were also determined.
The left middle part of the middle temporal gyrus (MTG) was significantly thinner in schizophrenia patients with AVHs than in patients without AVHs and healthy controls. Inferences were made using a false discovery rate approach with a threshold at p < 0.05. Left MTG thickness did not differ between patients without AVHs and controls. These results were replicated by a meta-analysis showing them to be consistent across the four centers. Cortical thickness of the left MTG was also found to be inversely correlated with hallucination severity across all schizophrenia patients.
The results of this multi-center study suggest that an abnormally thin left MTG could be involved in the pathogenesis of AVHs in schizophrenia.
The objective of this study was to determine how much improvement red edge-based vegetation indices (VIs) obtained with the RapidSCAN sensor would achieve for estimating rice nitrogen (N) nutrition index (NNI) at stem elongation stage (SE) as compared with commonly used normalized difference vegetation index (NDVI) and ratio vegetation index (RVI) in Northeast China. Sixteen plot experiments and seven on-farm experiments were conducted from 2014 to 2016 in Sanjiang Plain, Northeast China. The results indicated that the performance of red edge-based VIs for estimation of rice NNI was better than NDVI and RVI. N sufficiency index calculated with RapidSCAN VIs (NSI_VIs) (R2=0.43–0.59) were more stable and more strongly related to NNI than the corresponding VIs (R2=0.12–0.38).
This study aimed to examine the effectiveness of intratympanic methylprednisolone perfusion as salvage treatment for profound idiopathic sudden sensorineural hearing loss.
A retrospective clinical study of 97 patients with unilateral profound idiopathic sudden sensorineural hearing loss was performed. In all, 83 patients who received salvage intratympanic methylprednisolone perfusion plus conventional treatment (except for steroids) as the second-line therapy were assigned to the study group, while 14 patients who received conventional treatment alone were assigned to the comparison group.
In the study group, treatments in patients with a shorter interval from disease onset to intratympanic methylprednisolone perfusion (up to 15 days) had significantly greater improvements in the overall effective rate and pure tone average compared with patients with a longer interval (over 15 days). For patients with a short interval from disease onset to intratympanic methylprednisolone perfusion, those in the study group had significantly greater improvements in the overall effective rate and pure tone average compared with those in the comparison group. In both the study and comparison groups, hearing improvements were greater at low frequencies than at medium and high frequencies.
The interval from disease onset to intratympanic methylprednisolone perfusion was the major factor affecting hearing recovery. Early second-line salvage intratympanic methylprednisolone perfusion significantly improved the degree of hearing recovery in profound idiopathic sudden sensorineural hearing loss patients after failure of systemic steroid treatment.
Poor insight is prevalent in patients with schizophrenia and has been associated with acute illness severity, medication non-adherence and poor treatment outcomes. Paradoxically, high insight has been associated with various undesirable outcomes, including low self-esteem, depression and low subjective quality of life (QoL) in patients with schizophrenia. Despite the growing body of studies conducted in Western countries supporting the pernicious effects of improved insight in psychosis, which bases on the level of self-stigma, the effects are unclear in non-Western societies. The current study examined the role of self-stigma in the relationship between insight and psychosocial outcomes in a Chinese population.
A total of 170 outpatients with schizophrenia spectrum disorders were recruited from two general university hospitals. Sociodemographic data and clinical variables were recorded and self-report scales were employed to measure self-stigma, depression, insight, self-esteem and subjective QoL. Structural equation modelling (SEM) was used to analyse the cross-sectional data.
High levels of self-stigma were reported by 39% of the participants (n = 67). The influences of insight, self-stigma, self-esteem and depression on subjective QoL were confirmed by the SEM results. Our model with the closest fit to the data (χ2 = 33.28; df = 20; p = 0.03; χ2/df = 1.66; CFI = 0.98; TLI = 0.97; RMSEA = 0.06) demonstrated that self-stigma might fully mediate the association of insight with low self-esteem, depression and poor subjective QoL. High insight into illness contributed to self-stigma, which caused low self-esteem and depression and, consequently, low QoL. Notably, insight did not directly affect self-esteem, depression or QoL. Furthermore, the association of insight with poor psychosocial outcomes was not moderated by self-stigma.
Our findings support the mediating model of insight relevant to the poor psychosocial outcomes of individuals diagnosed with schizophrenia in non-Western societies, in which self-stigma plays a pivotal role. These findings elucidate the direct and indirect effects of insight on psychosocial outcomes and imply that identifying and correcting self-stigma in people with schizophrenia could be beneficial. Additional studies are required to identify whether several other neurocognitive or psychosocial variables mediate or moderate the association of insight with self-esteem, depression and QoL in patients with schizophrenia. Studies with detailed longitudinal assessments are necessary to confirm our findings.
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.