Attention contains three functional network subcomponents of alerting, orienting, and executive control. The attention network test (ANT) is usually used to measure the efficiency of three attention subcomponents. Previous researches have focused on examining the unimodal attention with visual or auditory ANT paradigms. However, it is still unclear how an auditory stimulus influences the visual attention networks. This study investigated the effects of bilateral auditory stimuli (Experiment 1) and ipsilateral auditory stimulus (Experiment 2) on the visual attention subcomponents. We employed an ANT paradigm and manipulated the target modality types, including visual and audiovisual modalities. The participants were instructed to distinguish the direction of the central arrow surrounded by distractor arrows. In Experiment 1, we found that the simultaneous bilateral auditory stimuli reduced the efficiency of visual alerting and orienting, but had no significant effect on the efficiency of visual executive control. In Experiment 2, the ipsilateral auditory stimulus reduced the efficiency of visual executive control, but had no significant effect on the efficiency of visual alerting and orienting. We also observed a reduced relative multisensory response enhancement (rMRE) effect in cue condition relative to no cue condition (Experiment 1), and an increased rMRE effect in congruent condition compared with incongruent condition (Experiment 2). These results firstly provide evidence for the alerting, orienting and executive control effects in audiovisual condition. And the bilateral and ipsilateral auditory stimuli have different effects on the subcomponents of visual attention. At every moment, we are bombarded with an overpowering amount of sensory information . Attention plays a main role in the cognitive processes of human as a mechanism that enables the selection of stimuli from a multitude of sensory information, and helps the brain integrate useful stimuli into coherent cognition . It is sOne classic procedure for simultaneously studying these three attention subcomponents is the attention network test (ANT) , which cDespite limited evidence in ANT, studies using other attention tests found that auditory stimuli could affect the alerting, orienting, or executive control network within the visual domain, respectively. Several findings have revealed that the response to multisensory  target could be faster and more accurate than response to unisensory  target, that is, the redundant signals effect . It has In the domain of executive control, previous studies have indicated that synchronized auditory stimuli might affect conflict resolving . LaurienAccording to the above, the role of auditory stimuli on the visual attention networks is complex and multifaceted. Nevertheless, in ANT paradigm, we are aware of only one research  involvinThe present study aims to examining the effect of auditory stimuli on the alerting, orienting and executive control networks of visual attention. Based on previous studies in which both bilateral and ipsilateral auditory stimuli could affect the orienting effect, while the executive control effect was only affected by ipsilateral auditory stimulus, we manipulated the sounds position. In Experiment 1, the visual target was presented simultaneously with bilateral auditory stimuli, which were presented by two peripheral speakers on the left and right of the screen. In Experiment 2, the visual target was presented simultaneously with ipsilateral auditory stimulus, which was presented by one peripheral speaker on the left or right side of the screen.In this task, the audiovisual stimuli consisted of visual stimuli accompanied by simultaneous bilateral or ipsilateral auditory stimuli. We manipulated the cue type , flanker type  and modality type , and compared the mean reaction times (RTs) and accuracy of the targets in the visual condition to the audiovisual condition. In accordance with previous researches, we suggested that the bilateral and ipsilateral auditory stimuli have different effects on the visual attention subcomponents. Specifically, based on the similar enhanced orienting effect has been found in visual detection tasks , we predM = 20.56 years, SD = 1.43) volunteered to participate in this study. Using the G*Power toolbox  display equipped with a screen resolution of 1366 × 768 pixels, and a refresh rate of 60 Hz. Visual stimuli were presented on a gray background screen  65 cm from the subjects. Auditory stimuli were presented via two speakers placed at both the left and the right of the screen (hidden behind the screen). MATLAB 2013b  and PsychToolbox-3  were useThe fixation stimulus was a black cross , displayed at the central location of screen. One of four different types of the cue prior to the target was presented: (1) no cue: no warning stimulus was presented prior to the target; (2) double cue: two asterisks appeared above and below the fixation cross; (3) center cue: an asterisk briefly replaced the fixation cross; (4) spatial cue: an asterisk appeared above or below the central fixation cross. The spatial cue could accurately predict the location of target. The visual stimuli consisted of a row of five horizontal black arrows, or a central arrow flanked with the left and right by two horizontal black lines, with arrowheads pointing leftward or rightward. The central arrow  was the target, and the other arrows or lines were flankers. The central arrow pointed to left or right, and the flanker arrows pointed in the same direction as the former (congruent condition); the central arrow pointed to left or right, while the flanker arrows pointed in the opposite direction (incongruent condition); or the central arrow pointed to left or right, which was flanked by horizontal black lines . The arrows appeared on above or below the fixed cross with equal probability.The auditory stimuli were 500 Hz pure tone (60 ms), which were presented simultaneously by the left and right speakers. The modality types could be unimodal visual  or audiovisual , shown in random with equal probability.The experiment manipulated three factors of cue type , flanker type  and modality type . Each trial started with the presentation of a fixation cross with a random duration between 400 and 1600 ms see . Followip2) was calculated for the ANOVA.Response accuracy and reaction times were collected as experimental data. All missing or false trials were removed from the data. Outliers were defined as three standard deviations (SD) above or below the mean reaction times, and were removed from the experimental data. The final data deletion accounted for 3.89% of the total data. A 4  × 3  × 2  repeated-measures ANOVA was conducted on the accuracy and reaction times. The Greenhouse–Geisser epsilon correction was used to correct for non-sphericity. The Bonferroni correction was applied to the post-hoc comparisons. The effect size of the partial eta squared (ηUsing mean reaction time (RT), a set of cognitive subtractions (described below) was used to assess the efficiency of three attention networks :Alerting effect = RT (no cue) – RT (double cue)Orienting effect = RT (center cue) – RT Executive control effect = RT (incongruent) – RT (congruent)d was used to report the effect sizes and all statistical levels  were set to 0.05.Median response times of each participant in each condition were used for further analyses. The relative multisensory responses enhancement (rMRE) value reflects the relative amount of acceleration or deceleration of the individual when responding to a multisensory modalities target as compared to when responding to a unimodal target. In Experiment 1, we asked participants to respond to V or AV, but did not set unimodal auditory trials. Thus, we calculated the rMRE using a single visual condition . The CohF  = 16.819, p < 0.001, ηp2 = 0.281], which was driven by participants responding more accurately to no cue (98.06%) than center cue  or double cue . The main effect of flanker type was significant , caused by participants responding more accurately to congruent condition (99.12%) than neutral condition  or incongruent condition . There was no main effect of modality type . A significant modality type and flanker type interaction  and a significant cue type and flanker type interaction  were revealed. No significant interaction was found in modality type and cue type . The three-way interaction between modality type, cue type, and flanker type was not significant .Accuracy was high with participants completing above 90% of trials correctly overall. A repeated 4 × 3 × 2 ANOVA with cue type , flanker type  and modality type  was conducted on accuracy. There was a main effect of cue type , indicating that participants responded more slowly in no cue condition (538.49 ms) than in double cue , center cue , and spatial cue conditions . In addition, participants responded more slowly in both double cue and center cue conditions than in spatial cue condition . There was a main effect of flanker type , caused by participants responding more slowly in the case of incongruent condition (544.62 ms) than in the case of neutral  and congruent conditions . The main effect of modality type was significant , which was driven by participants responding more slowly to visual modality than audiovisual modality (511.50 ms vs. 501.17 ms).A repeated 4 × 3 × 2 ANOVA with cue type , flanker type , and modality type  was conducted on reaction times. There was a main effect of cue type , which could be explained by differences in the sizes of cue effects for different modalities. There was also a significant interaction between modality type and flanker type , which could be explained by differences in the sizes of flanker effects for different modalities. A significant cue type and flanker type interaction  was revealed, and a three-way interaction between cue type, flanker type, and modality type was significant .The interaction between modality type and cue type was significant . The responses to the visual stimuli (527.90 ms) were slower than those to the audiovisual stimuli (514.58 ms). The main effect of cue type was also significant . The results showed that the responses in no cue condition (538.08 ms) were slower than those in double cue condition (504.39 ms), which suggested that alerting effect occurred. There was a significant interaction between modality type  and cue type  . The value of alerting effect under visual condition  was significant bigger than audiovisual condition  = 3.347, p = 0.002, d = 0.487, 95% CI = )  × 2  repeated-measures ANOVA showed that the main effect of the modality type was significant [75]) see .F  = 36.847, p < 0.001, ηp2 = 0.461]. The responses to the visual stimuli (493.69 ms) were slower than those to the audiovisual stimuli (486.15 ms). The main effect of cue type was also significant . The results showed that the responses in center cue condition (506.78 ms) were slower than those in spatial cue condition (473.06 ms), which suggested that orienting effect occurred. There was a significant interaction between modality type  and cue type  . The value of orienting effect under visual condition  was significant bigger than audiovisual condition  = 3.599, p = 0.001, d = 0.325, 95% CI = )  × 2  repeated-measures ANOVA showed that the main effect of the modality type was significant [05]) see .F  = 68.872, p < 0.001, ηp2 = 0.616]. The responses to the visual stimuli (520.05 ms) were slower than those to the audiovisual stimuli (510.47 ms). The main effect of flanker type was also significant . The results showed that the responses in incongruent condition (544.38 ms) were slower than those in congruent condition (486.14 ms), which suggested that executive control effect occurred. However, there was no significant interaction between modality type and flanker type . The value of executive control effect under visual condition  was analogous to that under audiovisual condition  = 2.000, p = 0.052, d = 0.201, 95% CI = )  × 2  repeated-measures ANOVA showed that the main effect of the modality type was significant [67]) see .M = 3.10 ms, SD = 2.57 ms, t (43) = 8.014, p < 0.001, d = 1.206; double cue: M = 1.54 ms, SD = 2.54 ms, t (43) = 4.007, p < 0.001, d = 0.606; center cue: M = 1.62 ms, SD = 2.76 ms, t (43) = 3.893, p < 0.001, d = 0.587; spatial cue: M = 0.85 ms, SD = 2.31 ms, t (43) = 2.441, p = 0.019, d = 0.368]. Significant rMRE was observed in all flanker conditions as indicated by one-sample t-tests .Significant rMRE was observed in all cue conditions as indicated by one-sample t-tests . Planned pairwise comparisons indicated that rMRE was significantly larger in the no cue condition compared to the double cue , the center cue , and the spatial cue conditions . The main effect of flanker type was not significant  . The sample size calculated using G*Power toolbox was the same as Experiment 1. All participants reported normal or corrected-to-normal vision, no hearing impairment, no reported history of attention deficit disorder, and no history of brain damage. Before the experiment, all participants gave written informed consent. The study was conducted according to the ethical guidelines of the Liaoning Normal University Ethics Committee.Forty-eight healthy participants took part in the experiment and one participant was excluded for failing to attain 80% on accuracy rate. The final sample consisted of forty-seven undergraduate University students aged 19–27 years  above or below the mean reaction times, and were removed from the experimental data. In Experiment 2, the final data deletion accounted for 3.08% of the total data.F  = 8.744, p < 0.001, ηp2 = 0.160], which was driven by participants responding more accurately to spatial cue (98.65%) than center cue . The main effect of flanker type was significant , caused by participants responding more accurately to congruent condition (99.45%) than neutral condition  or incongruent condition . There was a main effect of modality type , indicating that participants responding more accurately in audiovisual modality compared to visual modality (98.42% vs. 97.89%). A significant modality type and flanker type interaction  and a significant cue type and flanker type interaction  were revealed. No significant interaction was found in modality type and cue type . The three-way interaction between modality type, cue type, and flanker type was not significant .Accuracy was high with participants completing above 90% of trials correctly overall. A repeated 4 × 3 × 2 ANOVA with cue type , flanker type  and modality type  was conducted on accuracy. There was a main effect of cue type , indicating that participants responded more slowly in no cue condition (497.13 ms) than in double cue , center cue , and spatial cue conditions . In addition, participants responded more slowly in both center cue and double cue conditions than in spatial cue condition . There was a main effect of flanker type , caused by participants responding more slowly in the case of incongruent condition (522.39 ms) than in the case of neutral  and congruent conditions . The main effect of modality type was significant , which was driven by participants responding more slowly to visual modality than audiovisual modality (507.09 ms vs. 455.52 ms).A repeated 4 × 3 × 2 ANOVA with cue type , flanker type , and modality type  was conducted on reaction times. There was a main effect of cue type , which could be explained by differences in the sizes of flanker effects for different modalities. A significant cue type and flanker type interaction  was revealed, and a three-way interaction between cue type, flanker type, and modality type was significant . However, the interaction between modality type and cue type was not significant .The interaction between modality type and flanker type was significant . The responses to the visual stimuli (516.15 ms) were slower than those to the audiovisual stimuli (462.40 ms). The main effect of cue type was also significant . The results showed that the responses in no cue condition (496.52 ms) were slower than those in double cue condition (482.03 ms), which suggested that alerting effect occurred. However, there was no significant interaction between modality type  and cue type  . The value of alerting effect under visual condition  was analogous to that under audiovisual condition  = 0.671, p = 0.506, d = 0.140, 95% CI = )  × 2  repeated-measures ANOVA showed that the main effect of the modality type was significant [11]) see .F  = 29.629, p < 0.001, ηp2 = 0.392]. The responses to the visual stimuli (496.51 ms) were slower than those to the audiovisual stimuli (477.45 ms). The main effect of cue type was also significant . The results showed that the responses in center cue condition (481.72 ms) were slower than those in spatial cue condition (462.23 ms), which suggested that orienting effect occurred. However, there was no significant interaction between modality type  and cue type  . The value of orienting effect under visual condition  was analogous to that under audiovisual condition  = 1.651, p = 0.106, d = 0.273, 95% CI = )  × 2  repeated-measures ANOVA showed that the main effect of the modality type was significant [11]) see .F  = 28.021, p < 0.001, ηp2 = 0.379]. The responses to the visual stimuli (515.88 ms) were slower than those to the audiovisual stimuli (466.01 ms). The main effect of flanker type was also significant . The results showed that the responses in incongruent condition (522.19 ms) were slower than those in congruent condition (459.69 ms), which suggested that executive control effect occurred. There was a significant interaction between modality type and flanker type . The value of executive control effect under audiovisual condition  was significant bigger than visual condition  = 2.833, p = 0.007, d = 0.454, 95% CI = )  × 2  repeated-measures ANOVA showed that the main effect of the modality type was significant [43]) see .M = 10.50 ms, SD = 10.95 ms, t (46) = 6.574, p < 0.001, d = 0.959; double cue: M = 10.61 ms, SD = 13.18 ms, t (46) = 5.520, p < 0.001, d = 0.805; center cue: M = 10.31 ms, SD = 12.85 ms, t (46) = 5.502, p < 0.001, d = 0.802; spatial cue: M = 9.39 ms, SD = 12.58 ms, t (46) = 5.114, p < 0.001, d = 0.746]. Significant rMRE was observed in all flanker conditions as indicated by one-sample t-tests .Significant rMRE was observed in all cue conditions as indicated by one-sample t-tests . There was a main effect of flanker type . Planned pairwise comparisons indicated that rMRE was significantly smaller in the incongruent condition compared to the neutral condition , and the congruent condition . . Third, value of executive control effect in the audiovisual condition was significantly larger than those in the visual target condition see . The valNo matter with or without accompanying sound, the reaction times were significantly longer at incongruent flanker condition than congruent or neutral flanker condition. While there was no significant difference between neutral flanker and congruent flanker conditions . It suggThe primary goal of this study was to investigate the effects of bilateral and ipsilateral auditory stimuli on the subcomponents of visual attention. The results showed the bilateral auditory stimuli reduced the efficiency of visual alerting and orienting, but had no significant effect on the efficiency of visual executive control (Experiment 1). The ipsilateral auditory stimulus reduced the efficiency of visual executive control, but had no significant effect on the efficiency of visual alerting and orienting (Experiment 2). The results of Experiment 1 also showed a larger rMRE  at no cue condition compared with cue conditions. While, the results of Experiment 2 showed a larger rMRE at congruent condition compared with incongruent condition. Taken together, the bilateral and ipsilateral auditory stimuli have different effects on the subcomponents of visual attention.Participants were instructed to distinguish the direction of visual target arrow in both Experiment 1 and Experiment 2. The difference between two experiments was whether the auditory stimuli contained spatial information associated with the direction of visual target arrow. As we known, temporally synchronized auditory stimuli can facilitate participants’ performance on visual tasks . Making The bilateral auditory stimuli provided only temporal information related to the presentation for the visual target  and cuesUnlike bilateral auditory stimuli, ipsilateral auditory stimulus provided not only temporal information for the appearance of visual target, but also spatial information consistent with the direction of the target arrow . In ExpeResults from Experiment 1 found that relative multisensory response enhancement was decreased at cue conditions compared with no cue condition, but there was no difference in all flanker conditions. Results from Experiment 2 found that relative multisensory response enhancement was decreased at incongruent condition compared with congruent condition, but there was no difference in all cue conditions. The multisensory stimuli congruence is a critical factor in multisensory behavioral performance. Previous studies have shown that incongruent stimuli have an effect on the modulation of multisensory integration . Li et aInvestigating the alerting, orienting and executive control of attention networks can benefit us to understand attentional deficits and psychiatric disorders. For example, In summary, the current results clearly provide the first empirical evidence for the alerting, orienting and executive control effects in audiovisual condition. Both the bilateral and ipsilateral auditory stimuli affect the efficiency of visual attention networks, but the affected subcomponents are different. The bilateral auditory stimuli provide temporal information related to the presentation for visual target, which weaken the role of cues and affect visual alerting and orienting efficiency specifically. The ipsilateral auditory stimulus provides not only temporal information but also spatial information consistent with the direction of the target arrow, which affects the executive control effect. Specifically, the ipsilateral auditory stimulus increases the difference in response time between congruent and incongruent conditions. We also found a reduced rMRE effect at cue conditions compared with no cue condition, and a larger rMRE effect at congruent condition compared with incongruent condition. Finally, the results help to further illuminate how we resolve the conflicts of multisensory scenes in our daily life.


Long‐acting somatostatin analogs, including lanreotide slow release (LAN‐SR) and octreotide long‐acting release (OCT‐LAR), can improve hypoglycemia in insulinoma. LAN‐SR may be more beneficial in some patients with insulinoma than OCT‐LAR. Long‐acting somatostatin analogs, including lanreotide slow release (LAN‐SR) and octreotide long‐acting release (OCT‐LAR), can improve hypoglycemia in insulinoma. LAN‐SR may be more beneficial in some patients with insulinoma than OCT‐LAR. Although surgical resection is the primary treatment modality, medical treatments that alleviate hypoglycemia are essential for treatment of inoperable conditions, including advanced disease or tumors with unknown primary sites.2A 36‐year‐old Japanese man was admitted to our hospital for suspected insulinoma and an intolerance to diazoxide. The details of the patient's clinical course with respect to glycemic responses to diazoxide have been previously reported.After 3 years, the patient developed refractory hypoglycemia, requiring higher doses of diazoxide , as well as chronic side effects, including systemic edema and pleural effusion. He was subsequently admitted to our hospital for treatment reevaluation and lesion relocalization for surgical resection.2.1Endogenous hyperinsulinemic hypoglycemia may be present, when the laboratory data fulfill the following conditions: blood glucose <55 mg/dL, insulin >3 μU/mL, and C‐peptide >0.6 ng/dL.Figure Serum C‐peptide levels were reduced both by LAN‐SR (from 0.8 to 0.2 mg/dL) and the first administration of OCT‐LAR , which antagonize the effects of insulin. OCT has been reported to paradoxically aggravate hypoglycemia in some patients with insulinoma,Lanreotide and OCT inhibit GH and glucagon secretion; however, differences in the efficacies of LAN and OCT have been reported. In a prospective crossover study comparing the efficacy of LAN‐SR and OCT‐LAR in 10 patients with acromegaly, OCT‐LAR decreased GH levels 12% more than LAN‐SR after 6 months of treatment.There are some limitations to this report. First, we did not measure circulating GH, IGF‐1, or glucagon levels, which would be necessary to prove our hypothesis. Second, we did not perform a crossover comparison between the two drugs with a longer observation period, because the tumor was successfully identified for surgical resection. Third, we cannot rule out the possibility that LAN and OCT might inhibit the secretion of gastrointestinal hormones and exert different effects on glycemic control by differentially affecting nutrient absorption.In conclusion, the effects of LAN‐SR and OCT‐LAR on blood glucose levels in hypoglycemic patients with insulinoma may differ. LAN‐SR may be more useful than OCT‐LAR in alleviating hypoglycemia that is refractory to traditional medical therapy in patients with insulinoma.The authors declare no conflicts of interest.KY and SN: contributed to the patient's clinical care and preparation of the manuscript. NO, NSaw, SS, MT, KO, and KEb: contributed to the patient's clinical care and revision of the manuscript. KEn, MK, HS, and NSat: contributed to patient's surgery and revision of the manuscript. AK and NF: contributed to the histopathological assessment and revision of the manuscript. SI: contributed to the patient's clinical care, revision, and final approval of the manuscript of the manuscript. All authors approved the final manuscript.Because of the patient's inability to understand instructions due to cerebral palsy, written informed consent was obtained from the patient's parents for publication of this case reports and any accompanying images.


This study investigated whether priests’ attitudes regarding individuals with schizophrenia and depression participating in religious practices varied in relation to priests’ adherence to prejudices about these mental disorders (MD). A sample of 559 Italian priests completed a questionnaire on their views of either schizophrenia or depression. Data were analyzed using a multiple-group structural equation in which the diagnostic group was a moderator and the size of the municipalities in which the churches were located was a covariate. The study revealed that: priests’ attitudes towards churchgoers with MDs are related to views of these individuals as dangerous, easy to recognize and poorly aware of their MDs; community size has a direct effect on priests’ attitudes and an indirect effect through perceived dangerousness; the above-mentioned relationships do not differ by type of disorder. Sensitizing priests on stigma may be helpful to facilitate the participation of believers with MDs to religious practices. Approximately 85% of people worldwide identify with a religion, mostly Christianity and Islam Hackett, . In lineWithin the religious community, priests go beyond a spiritual role, frequently acting as personal advisors in non-religious matters   and voluntary activities , and to receive individual spiritual support , advices , and economic help (27.3% and 34.8%). Further details on the descriptive data are reported in Magliano et al.  refused to participate in the study  and 559 agreed to participate (91.8%). Of these, 282 completed the OQ-P after reading a description of schizophrenia and 277 completed the questionnaire after reading a description of depression. In both groups, most participants were middle-aged (53.04 ± 12.8 and 52.3 ± 13.9 years old), had a bachelor’s degree in theology (78.0% and 69.3%), and had been priests for over two decades (22.9 ± 13.8 and 22.4 ± 15.1 years). Nearly all participants (90.1% and 96.8%) stated they knew individuals with MDs attending the church to participate in celebrations (58.2% and 57.3%), religious groups  recommended professionals. Six “yes/no” items on health and religious professionals to be involved in the treatment of MD; (c) psychosocial consequences of MDs. Twenty-seven items, rated on a 3-point scale from 1= “not true” to 3= “completely true”, and grouped into the following thirteen factors: c.1) possibility of recovery in MDs (1 item); c.2-c.3) usefulness of pharmacological and psychological therapies in MDs ; c.4) need for long-term pharmacological therapies (3 items); c.5-c.6) usefulness of prayer and exorcism as therapies for MDs ; c.7) poor insight of people with MDs into their condition (2 items); c.8-c.9) perception of social distance from and dangerousness of people with MDs ; c.10) difficulties of people with MDs in affective relationships (2 items); c.11) easy recognizability of people with MDs (1 item); c.12) participation of people with MDs in parish activities and sacraments (4 items); c.13) discriminatory behaviors in religious celebrations (3 items). Regarding the factor named “recognizability” (c.11), it refers to respondent’s views about people with MDs as easy to recognize on the basis of appearances, gestures and behaviors considered unusual and/or peculiar to a given “type” of people. Concerning the factor named “discriminatory behaviors in religious celebrations” (c.13), it refers to respondent’s views about the opportunity to treat people with MD differently from other believers during the celebrations . In this factor’s items the term “discriminatory” is not used to avoid potential bias in the answers. The psychometric properties of the OQ-P, previously tested on the global sample of 559 priests, were found to be satisfactory , χ2(558) = 341.86, df 160, p < .001; non-normed fit index [NNFI] = 0.93; comparative fit index [CFI] = 0.94; root mean square error of approximation [RMSEA] = 0.04, 90% C.I. ; standardized root mean square residual [SRMR] = 0.05; all factor loadings significant at p < .001 level; Cronbach’s α values of the factors ranging from 0.48 to 0.75. Section c: CFA, χ2(559) = 559.13, df 252 p < .05; non-normed fit index [NNFI] = 0.91; comparative fit index [CFI] = 0.93; root mean square error of approximation [RMSEA] = 0.05, 90% C.I. ; standardized root mean square residual [SRMR] = 0.05; all factor loadings significant at p < .001 level. Cronbach’s α values ranging from 0.52 to 0.84). For each OP-Q factor, an average score is computed. Single factor scores are not combined into a total overall score as not all factors correlated significantly with each other  included the following sections on priest’s views on: (a) causes of MDs. Twenty 2) was used to test the relative fit of nested models . Bivariate correlations were performed by SPSS version 21 , Pearson’s correlation coefficient was computed to explore bivariate relations between the mean scores of the six OQ-P factors mentioned above and the community size of the municipalities where the churches were located . A multiple-group structural equation model was used to test the hypothesized relations among the following OQ-P factors: perception of social distance from people with MDs; perception of dangerousness; easy recognizability of people with MDs (independent observed variables) with the following OQ-P factors: participation of people with MDs in parish activities and sacraments; discriminatory behaviors in religious celebrations (dependent observed variables). In the model, type of disorder (schizophrenia and depression) was used as grouping variable (moderator) and community size was included as covariate influencing all the observed variables. Model fit was determined by computing the following indexes: Comparative Fit Index , “kept at a distance by the others”’, , and ‘dangerous to others’ (77.0% and 72.0%). Most priests thought it was ‘completely true’ or ‘partially true’ that people with these disorders were “reliable when they confess” (88.1% and 90.5%) and able to be “witnesses in the sacraments ” (87.4% in both groups). 51.8% of priests in the schizophrenia group and 43.9% of priests in the depression group believed that, during religious celebrations, people with MDs created “discomfort to other churchgoers”, and 46.6% and 37.1% of priests believed that these individuals “should be supervised”.As shown in Table In both the schizophrenia group and the depression group, priests’ perception of dangerousness and of social distance from people with MDs, and community size positively correlated with priests’ views regarding the opportunity to treat persons with MD differently from other churchgoers during religious celebrations  = 0, p = .0, RMSEA = 0.0 , TLI = 1, CFI = 1 (saturated model). During the second step of the analysis, structural paths and correlations were constrained to be equal across the diagnostic groups. The fit indices for the constrained model were as follows: χ2(21) = 18.20, p = .63, RMSEA = 0.0 , TLI = 1, CFI = 1. The delta chi-square statistic showed that the fit of the constrained model across diagnostic groups was significantly better than the fit of the unconstrained model, Δχ2(21) = 18.20, p > .05. Therefore, the constrained model with total invariance across diagnostic groups was adopted. In line with our hypothesis . It may seem odd that the relationships between the variables were equivalent between the two groups when analyzed in the path analysis, whereas they were different when analyzed with the bivariate correlations in each group. This apparent discrepancy can be explained by the fact that the correlations analyze two variables at a time and in individual samples, whereas the multigroup model analyses the relationships simultaneously between all variables within and between groups. Interestingly, bivariate correlations showed a relationship between perceived dangerousness and population size only in the depression group. One possible explanation could be that in rural centers, close relationships among community members would facilitate contact with people with depression, a mental disorder with high social acceptance, mitigating perceived dangerousness.This study showed that priests’ attitudes regarding people with MDs participating in religious activities are significantly related to priests’ views about this group of people as dangerous, easy to recognize and as having poor insight. The study also revealed that community size has both a direct effect on priests’ attitudes and an indirect effect through priests’ perception of dangerousness in people with MDs. Finally, the study revealed that the above-mentioned relationships do not differ by the type of disorder. This is only true when these relationships are analyzed within a multiple-group structural equation model  and priests’ views about the opportunity to adopt discriminatory behaviors toward persons with MD during celebrations. These data are in line with those reported by Leavey et al.  about thThe results of this study may contribute to a greater understanding of the relationships among the components of stigma, particularly those between priests’ views of people with MD and priests’ attitudes toward the participation of this group of people in religious activities. These results may have practical relevance and point to potential areas for intervention within religious communities. Countering priests’ stereotypes about dangerousness and poor insight to MDs could reduce the proportion of priests who tend to discriminate against churchgoers because of their MDs . The use of a validated self-reported questionnaire is a further strength, also facilitating replication of the survey. The study has a few limitations, suggesting caution in interpretation of its results. In particular, it should be considered that: (a) the inclusion of priests from only Southern Italy may limit the generalizability of the results to other geographical contexts. In this geographical area, the percentages of Catholics and of Catholics regularly attending churches are higher than in the country as a whole (78.5% vs. vs. 66.7%; 30.9% and 25.1%; Doxa,


In mental health care, patients and their care providers may conceptualize the nature of the disorder and appropriate action in profoundly different ways. This may lead to dropout and lack of compliance with the treatments being provided, in particular in young patients with more severe disorders. This study provides detailed information about patient–provider (dis)agreement regarding the care needs of children and adolescents.n = 123) with a youth-ACT sample (n = 121), we were able to assess the influence of severity of psychiatric and psychosocial problems on the extent of agreement on patient’s unmet care needs.We used the Camberwell Assessment of Need (CANSAS) to assess the met and unmet needs of 244 patients aged between 6 and 18 years. These needs were assessed from the perspectives of both patients and their care providers. Our primary outcome measure was agreement between the patient and care provider on unmet need. By comparing a general outpatient sample (k = 0.113) and “information regarding diagnosis/treatment” (k = 0.171). Comparison of the two mental healthcare settings highlighted differences for three-quarters of the unmet care needs that were examined. Agreement was lower in the youth-ACT setting.In general, patients reported unmet care needs less often than care providers did. Patients and care providers had the lowest extents of agreement on unmet needs with regard to “mental health problems” (Clarification of different views on patients’ unmet needs may help reduce nonattendance of appointments, noncompliance, or dropout. Routine assessment of patients’ and care providers’ perceptions of patients’ unmet care needs may also help provide information on areas of disagreement. Over 40% of the children and adolescents who use mental healthcare terminate treatment prematurely, do not comply with treatment, or do not attend appointments regularly , 2. AlthWe defined a “care need” as a physical, psychological, social, or environmental demand for aid, care or service intended to resolve a problem that a patient or his/her care provider perceived and expressed . Care nePrevious studies show that children and adolescents differ considerably from care providers with regard to the presence of psychiatric problems –18. CareThere is currently little or no research on the extent to which children and adolescents agree or disagree with care providers on the broad range of met and unmet care needs. Therefore, the aim of our study was to obtain insight into the extent of agreement on these needs between the two groups. Further, we aimed to better understand whether the extent of agreement would differ between two setting with a different treatment intensity.We had two a priori hypotheses: (1) that patients in the two settings would report less unmet care needs than their care providers; and (2) that we would find more disagreements between patients and care providers on the presence of patients’ unmet care needs in a youth-ACT setting—in other words, in a setting where patients had more severe psychiatric problems and psychosocial difficulties.In two different mental healthcare settings characterized by different severities of psychiatric problems and psychosocial difficulties, we used a cross-sectional design to compare the extent of agreement and disagreement between patients and mental healthcare providers on reported unmet care needs.To increase our insight into the extent of agreement regarding these needs, we first established their frequencies in a specialized mental healthcare setting, approaching them from the perspectives of children and adolescents and also from those of care providers. We then examined the extent of agreement on these needs between the two groups. To better understand how the extent of agreement on patients' unmet care needs was influenced by the severity of psychiatric problems and by psychosocial difficulties, we compared unmet care needs between two treatment settings . For thiThe study was performed in a specialized treatment center for child and adolescent psychiatry in the Netherlands. Patients and care providers were included from two settings that provided care for the same catchment area.The first was a general outpatient treatment setting (with low to moderate treatment intensity), in which treatment was provided by a multidisciplinary team consisting of one child psychiatrist, six psychologists, and one nurse practitioner, who made diagnostic assessments and provided cognitive behavioral therapy, eye-movement desensitization, and reprocessing therapy (EMDR); family support; and pharmacological treatment.The second was a youth-ACT setting (Assertive Community Treatment with high treatment intensity) consisting of one child psychiatrist, five psychologists, three nurse practitioners, and two mental health nurses. This team offered home-based outreach-oriented treatment to patients with more severe psychiatric and psychosocial problems. Care providers had small shared caseloads (< 15 patients) and provided outreaching case management, early intervention, cognitive behavioral therapy, EMDR, family support, and pharmacological treatment. The intensity of ACT treatment was scaled up or down according to the severity of a patient’s current psychiatric symptoms and psychosocial impairments.n = 2), they refused to participate (n = 6), or were referred to the youth-ACT setting during the inclusion period (n = 2). For the youth-ACT sample, we initially selected all patients who were referred from a general outpatient setting to this ACT treatment setting during the inclusion period (n = 169). Thereafter, 48 ACT patients had to be excluded because they did not meet the inclusion criteria: 27 patients because their sibling was already included in the study, 12 patients were not referred to the ACT setting from the outpatient setting, but by the general practitioner instead, and 9 patients refused to participate. The final sample consisted of 244 patients: 123 in the outpatient sample and 121 in the youth-ACT sample.Figure + Institute for Health and Care Research Amsterdam. Approval was also provided by the local scientific review board of the participating mental health institution.The study was reviewed and approved by the Medical Ethical Committee at VU University Medical Centre Amsterdam (protocol no. 2015.245) and by the Scientific Committee at the EMGOSeparately, children/adolescent participants, and their parents received written and oral information on the research project. In accordance with prevailing Dutch legislation, written consent from parents and/or children/adolescents was obtained as follows: (i) if children younger were aged less than 12, only parents were asked for consent for; (ii) if children were aged between 12 and 16, parents and children were both asked for consent; and (iii) if adolescents were 16 years or older, informed consent was obtained from them alone.The Demographic Information Questionnaire (DEMOG) was used to measure the following four demographic characteristics of each child or adolescent: (1) age, (2) gender, (3) country of birth, and (4) living in a single-parent family or a two-parent family .The Neuropsychiatric Interview for Children and Adolescent (MINI-KID) was used to assess patients’ psychiatric diagnoses , which wThe Camberwell Assessment of Need Short Appraisal Schedule (CANSAS) was used to assess the patient’s care needs as they were perceived both by the child/adolescent and by the mental healthcare provider . CANSAS t test for continuous variables, or using the Chi-square test with Yates continuity correction (χ2 test) for categorical variables. As an alternative to the Chi-square test, Fisher’s exact test was computed if the number in at least one of the cells of the categorical variable was lower than 5 [The participants’ demographics were analyzed using descriptive statistics, first for the entire sample and then separately for the two subgroups . Subgroup differences regarding age, gender, country of birth, general functioning, and living situation were analyzed using the r than 5 .To analyze the extent of agreement between patients and care providers at item level, Cohen’s kappa coefficients were computed for the overall sample and then separately for the two treatment settings. On the basis of the Cohen’s kappa values, the extent of agreement was categorized as follows: poor (≤ 0.20); fair (0.21–0.40); moderate (0.41–0.60); good (0.61–0.80); or very good (≥ 0.81–1.00) .p < 0.05 was considered to be statistically significant [To determine whether patient and care provider agreed or disagreed on the presence of an unmet need, the following calculation was made for both settings at CANSAS-item level: only the patient reported an unmet care need (P > CP); patient and care provider both reported the presence or absence of an unmet care need (P = CP); or only the care provider reported an unmet care need (P < CP) (see Table nificant .p < 0.05).Table p < 0.05). There were no significant differences between the two samples regarding age, gender, and country of birth.In the subsample of youth-ACT patients significantly higher frequencies were found for ASD (39.7%), mood (37.2%), behavior (29.8%), somatoform (13.2%), and personality (2.9%), indicating higher levels of comorbidity in patients treated in youth-ACT. Significantly more of those receiving ACT treatment reported growing up in a single-parent family (42.3%) than those receiving regular outpatient treatment  that were calculated to determine the agreement between patients and care providers in the overall sample at CANSAS item level. In general, patients reported unmet care needs less than care providers did. Below, our results are presented using the ICF domains, but, for purpose of conciseness, we now report only the results whose frequency in at least one of the two settings (outpatient or youth-ACT) was higher than 10%.Table k = 0.113), with the scores between patients (63.9%) and care providers (93.5%) differing significantly (p < 0.05). Agreement on unmet care need for “information regarding diagnosis/treatment” was also poor (k = 0.171), with patients (54.5%) reporting unmet needs significantly less than care providers . Agreement on “danger to others” was fair (k = 0.277), with patients reporting significantly fewer unmet needs (7.8%) than care providers . Agreement was also fair with regard to “danger to themselves” (k = 0.271), with patients reporting 7.4% and providers reporting 24.9% (p < 0.05). Agreement on unmet care needs related to “psychotic symptoms” was moderate (k = 0.438), with no significant differences between the two groups (patients 7.8% vs. providers 10.6%). Agreement for “medication side effects” was good . Agreement on physical functions was moderate for unmet needs related to “physical handicap or disease” . Finally, agreement on “quality or quantity of food” was only fair (k = 0.380), with no significant differences between the two groups (patients 7.8% vs. providers 12.7%).Agreement between patients and care providers on unmet needs for “mental health problems”—the most reported unmet care need—was poor (k = 0.328); the difference between patients (9%) and care providers (21.6%) was statistically significant (p < 0.05). Agreement on “cleaning up room or bedroom” was also fair . Agreement on “handling money” was moderate , as was agreement on “paid job or side job” , with no significant difference between the two groups. Agreement on unmet needs regarding “reading and writing skills at expected grade level” was good (k = 0.687), with no significant difference between patients (13.4%) and care providers (15.5%).Patient–provider agreement on abilities of self-care  as an unmet care was fair . With regard to “making and/or keeping friends” as an unmet care need, patients, and care providers reported significantly differently, leading to only fair agreement . Agreement on unmet needs related to “regular/suitable school or other daytime activities”  were moderate (k = 0.437), with significant differences between patients (23.0%) and providers . Patient–provider agreement for unmet care needs related to “intimate relations” was moderate (k = 0.561), with patients (7.4%) reporting significantly fewer unmet care needs related to “intimate relations” than care providers . Agreement on the presence of unmet needs related to “sexuality” was only poor .Agreement on “future prospects” —a frequently reported unmet need—was fair (Comparison of youth-ACT and outpatient clinics showed significant differences between the two settings for three-quarters of the unmet care needs that were investigated (see Table p < 0.05).As Table p < 0.05) in the outpatient sample.With regard to unmet care needs for “danger to others” and “danger to themselves,” patients and care providers  in the youth-ACT sample disagreed significantly more than patients and their care providers  between the two settings, with ACT patients (P < CP 14.2%) disagreements more on this item than outpatients (P < CP 2.4%).With regard to “quality and/or quantity of food”, there were significant differences  and those in the regular outpatient setting .p < 0.05). There were also significant differences (p < 0.05) between the youth-ACT sample and outpatient sample with regard to three unmet care needs: “cleaning-up room or bedroom” (youth-ACT P < CP 19.2% vs. outpatients P < CP 1.6%); “paid job or side job” ; and “handling money” (youth-ACT P < CP 12.5% vs. outpatients P < CP 2.4%).With regard to “abilities for self-care”, patients receiving youth-ACT treatment reported unmet care needs significantly less than their care providers (P < CP 25.0%), and significantly less than outpatients . Youth-ACT patients had significantly more patient–provider disagreements (p < 0.05) than outpatients with regard to unmet needs pertaining “future prospects” (youth ACT P < CP 45.0% vs. outpatients P < CP 22.0%); “regular/suitable school or other daytime activities” ; “sexuality” (youth-ACT P < CP 20.8% vs. outpatients P < CP 3.3%); and “intimate relations” (youth-ACT P < CP 15.0% vs. outpatients P < CP 0.8%).With regard to friendship-related unmet needs, patients in the youth-ACT sample scored significantly less than their care providers did (P < CP 50.8%), and significantly less than those receiving outpatient care  can be studied on different levels, e.g. (i) the problems experienced by the client; (ii) the interventions required to alleviate or limit these problems; (iii) the services required to provide these interventions. A specific problem can be solved (and related care needs can be met) by several different interventions, which can be applied by different types of services. Since the presence of a problem may require one or more interventions to ameliorate these problems, some authors suggested that needs should not only be assessed at the problem level, but also at the intervention level . In thisIn general, agreement between patients and care providers with regard to patients' unmet care needs was low . The first possible explanation for this is that the care provider obtained information not only from the child, but also from the parents, whose views on appropriate care needs often differ from those of their children –39. A seComparison of the youth-ACT setting with the general outpatient treatment setting showed significant differences with regard to three-quarters of the unmet care needs agreement regarding the care needs of children and adolescents who have been referred to general outpatient care and youth-ACT. This is a strength because children and adolescents with different severity levels of psychiatric problems were studied, which supported the generalizability of findings.A limitation of the study is its cross-sectional design, which prevented us from identifying causes of disagreements between patients and care providers on patients’ unmet care needs .We found that patients and care providers often disagreed on patients’ care needs, particularly in a youth-ACT treatment setting. Clarifying different views on patient’s unmet care needs may help to reduce nonattendance of appointments and early termination of treatment. Similarly, if patients and care providers systematically assessed patients’ unmet care needs, useful information may be provided on areas of disagreement. Future research should show whether better treatment outcomes would be produced by an approach focused on obtaining a shared view on unmet care needs.


Partial kidney ischemia-reperfusion (IR) injury is the principal cause of acute kidney injury. The renin-angiotensin system (RAS) and hypertension also may be influenced by renal IR injury. In two models of partial renal IR with and without ischemia preconditioning (IPC) and using Mas receptor (MasR) blockade, A779 or its vehicle, the renal vascular responses to angiotensin II (Ang II) administration in two-kidney-one-clip (2K1C) hypertensive rats were determined. −1.min−1) infusion using A779 or its vehicle were measured at constant renal perfusion pressure.  Thirty-seven 2K1C male Wistar rats with systolic blood pressure ≥150 mmHg were randomly divided into three groups; sham, IR, and IPC + IR. The animals in the sham group underwent surgical procedures except partial IR. The rats in the IR group underwent 45 min partial kidney ischemia, and the animals in the IPC + IR group underwent two 5 min cycles of partial kidney ischemia followed by 10 min reperfusion and partial kidney ischemia for 45 min. The renal vascular responses to graded Ang II  that was not different significantly between the groups. No significant differences were detected between the groups in renal blood flow (RBF) or renal vascular resistance (RVR) responses to Ang II infusion when MasR was not blocked. However, by MasR blockade, these responses were increased in IR and IPC + IR groups that were significantly different from the sham group (P < 0.05). For example, infusion of Ang II at dose 1000 ng kg−1.min−1 resulted in decreased RBF percentage change (RBF%) from the baseline to 17.5 ± 1.9%, 39.7 ± 3.8%, and 31.0 ± 3.4% in sham, IR, and IPC + IR, respectively.  Four weeks after 2K1C implementation, the intravenous infusion of graded Ang II resulted in dose-related increases in mean arterial pressure (MAP) ( These data revealed the important role of MasR after partial kidney IR in the responses of RBF and RVR to Ang II administration in 2K1C hypertensive rats. Kidney partial ischemia-reperfusion (IR) injury is defined as a reduction of the renal blood flow (RBF) followed by the recovery of RBF and reoxygenation . IR prom1R), and the nonconventional axis composed of Ang1-7 ACE2, Ang II type 2 receptor (AT2R), and Mas receptor (MasR) [1R has renoprotective effect in a number of kidney disorders, including AKI, hypertensive and diabetic nephropathy, glomerulonephritis, and tubulointerstitial fibrosis [The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure and fluid and electrolyte homeostasis , 10. Hypr (MasR) . The bior (MasR) . MasR asfibrosis , 15. In fibrosis .2R and MasR expression decrease in 2K1C [2R, and MasR [Two-kidney-one-clip (2K1C) as a model of renin-dependent hypertension and IR alter the balance between two axes of RAS –19. AT2R in 2K1C , while Iand MasR , 21, 22 and MasR . Therefoand MasR .1R and AT2R and alters the renal vascular responses to Ang II [There also is an interaction between the components of RAS. So, MasR not only acts as a specific receptor for Ang 1–7 but also interacts with ATo Ang II , 25. In o Ang II , 27.Accordingly, due to the alteration of RAS components by IR and hypertension and interaction between MasR with other receptors of RAS, we hypothesized that MasR may alter renal vascular response to Ang II administration in hypertensive rats that underwent IR with and without IPC. To prove the hypothesis, rats were subjected to 2K1C, 4 weeks later, under anesthesia, IR with and without IPC was implemented, and renal vascular responses to Ang II administration in the presence or absence of MasR were determined.n = 37, 246 ± 5 g, 7–8 weeks) were used in this study. The animals were obtained from the Water and Electrolyte Research Center, Isfahan University of Medical Sciences, Isfahan, Iran. The animals were kept in polyacrylic cages and maintained under standard laboratory conditions  with a 12 : 12 h light/dark cycle and free access to food and water. The protocol of this research was approved in advance by the Ethics Committee of Isfahan University of Medical Sciences (code# IR.MUI.REC.1397.345).Male Wistar rats  and xylazine . A 5 cm longitudinal incision was made on the right flank. The right kidney was exposed, and the renal artery was isolated from the renal vein. To induce 2K1C renovascular hypertension, the renal artery was clipped by placing a U-shaped silver clip (0.2 mm inner diameter) around it  to parti−1 i.p; Merck, Germany). After intubation of the trachea, the left jugular vein was catheterized by using a polyethylene catheter . Also, polyethylene catheters were inserted into the carotid and femoral arteries. Then, the animals were located in a lateral position, and after a transverse incision on the left side, the left kidney was isolated from the surrounding tissues and was placed in the kidney cup. The renal artery was isolated, and an ultrasonic probe was placed around it . Also, the abdominal aorta was isolated just between the branch of the renal and the iliac arteries, and an adjustable aortic clamp was placed around it to control renal perfusion pressure (RPP) during Ang II infusion and partial ischemia.Four weeks after renal artery clipping, the animals were anesthetized with urethane  for drug infusion. The carotid and femoral catheters were linked to a Powerlab System  to measure systolic blood pressure (SBP), mean arterial pressure (MAP), and RPP respectively . BesidesThe animals with SBP ≥150 mmHg were divided into three experimental groups of sham, IR, and IPC + IR. Following surgical procedures, the animals were allowed to stabilize and achieve equilibrium condition at least for 30 min. The SBP, MAP, RPP, RBF, and RVR were determined as baseline data which were obtained over the last 5 min of equilibrium that was called the “control” phase.After the control phase, the experiment was continued according to the type of experimental group. In the sham group; the animals were subjected to the surgery process without IR or IPC. In the IR group, the RPP was reached to about 25 mmHg by using an adjustable occluder and was considered as partial kidney ischemia. Therefore, IR induced by controlling RPP in the range of 25 ± 3 mmHg by tightening the abdominal aortic clamp for 45 min. In the IPC group, IPC induced by two 5 min cycles of partial ischemia and 10 min reperfusion was performed before partial kidney ischemia for 45 min. The mean values for MAP, RPP, RBF, and RVR were measured during partial kidney ischemia called the “Ischemia” phase.After 45 min of partial kidney ischemia, reperfusion was allowed by loosening the clamp, and the mean values for MAP, RPP, RBF, and RVR were measured at 1–3 min after beginning of reperfusion called the “Reperfusion1” phase.μg·kg−1 followed by continuous infusions of 50 μg·kg−1 [Then, the antagonist (A779) or its vehicle  was started to infuse with a microsyringe infusion pump  at 1–3 min after the beginning of reperfusion. Thirty minutes later, the data for MAP, RPP, RBF, and RVR were determined and were considered as an antagonist/vehicle effect called the “treat” phase. The A779  was injected with a bolus dose of 50  μg·kg−1  using a −1·min−1, while the vehicle or A779 infusion continued until the end of the experiment. Each dose of Ang II was injected for 15 min. The data were recorded during the last 3–5 min of each dose of Ang II administration that was considered as a vascular response to Ang II infusion.At 30 min after A779 or its vehicle administration, Ang II was infused in different doses of 30, 100, 300, and 1000 ng.kgFinally, the rats were humanely sacrificed by anesthetic overdose of urethane  infused via a left jugular vein catheter, and the left kidneys were removed and weighed immediately.P value ≤ 0.05 for the effect of graded Ang II (Pdose), the comparisons between groups (Pgroup), and the interaction between treatment and groups (Pdose×group) was considered as significant.The data are presented as mean ± SEM, and the analysis was performed using SPSS version 22 software. Comparison of the MAP, RPP, RBF, and RVR between sham, IR, and IPC + IR groups in control, ischemia, reperfusion1, and treat phases was performed using one-way ANOVA followed by the LSD post hoc test. Responses to graded Ang II administration were analyzed by ANOVA for repeated measures followed by the LSD post hoc test. The There were 4 phases of measurements before Ang II administration: control, ischemia, reperfusion1, and treat . MAP, RPAlthough there were observed statistical differences in RPP, RBF, and RVR between sham, IR, and IPC + IR during ischemia, no significant differences were detected between the groups in control and treat phases . These dThe intravenous infusion of graded Ang II resulted an increase of MAP in a dose- related manner in sham, IR, and IPC + IR groups receiving either A779 or its vehicle . HoweverAs mentioned before, RPP was kept constant by manipulation of the aortic clamp during Ang II injection. Therefore, no alteration in RPP by Ang II administration was expected. However, a little increase in RPP was detected in the sham group which received the vehicle which was not considered to be important.Pdose < 0.0001), but no significant difference in RBF% response to graded AngII infusion was detected between the groups. However, when MasR was blocked with A779, a significant difference between sham and other groups in the RBF% response to Ang II administration was observed  response to graded Ang II infusion in sham, IR, and IPC + IR groups which received the vehicle for antagonist decreased dose dependently (observed . For exaPdose < 0.0001), but no significant difference in RVR% response to graded AngII infusion was detected between the groups. However, when MasR was blocked with A779, a significant difference between sham and other groups in the RVR% response to Ang II administration was observed  in sham, IR, and IPC ± IR groups treated with the vehicle in a dose-dependent manner  blocker and enzyme (ACE) inhibitor to reduce kidney complications following cardiac surgery [The beneficial effects of IPC are seen in kidneys –43. IPC  surgery , and theKidney IR promoted the RBF and RVR responses to Ang II administration in 2K1C hypertensive rats when MasR was blocked. This effect may be related to vascular function alteration in the kidney after partial IR.


Lewy bodies are the pathological hallmarks of Parkinson's disease. There is a need for effective biomarker that is cost effective, less invasive, and easily reproducible with good sensitivity and specificity and can be used to diagnose the condition early and track its severity and progression. Alpha‐synuclein (α‐syn), an integral component of the Lewy body, is found in saliva and can be a potential answer to the above concerns.PubMed, EMBASE, Google Scholar, and CNKI databases, along with additional sites, were searched from January 2010 to August 2021. Standard mean difference (Hedges' g) with 95% CI was used to show an association. Statistical analysis was done using STATA software version 16 (StataCorp).We found a significant reduction in the mean difference of total salivary α‐syn among PD patients compared to healthy controls. However, the mean difference of oligomeric α‐syn and oligo/total salivary α‐syn ratio was significantly increased among PD patients compared to healthy controls.Our systematic review and meta‐analysis found that salivary α‐syn parameters  can be considered a simple, easy‐to‐use, cost‐effective, and reliable diagnostic biomarker for PD and its progression. Alpha‐synuclein parameters  can be considered as a simple, easy to use, cost‐effective, and reliable diagnostic biomarker for PD and its progression. Degeneration of dopaminergic neurons in the substantia nigra pars compacta and the formation of intracytoplasmic inclusions known as Lewy bodies (LB) are pathological hallmarks of Parkinson's disease.Alpha‐synuclein(α‐syn) aggregates are found in LB. The accumulation causes neuronal dysfunction and neuroinflammation. It has been shown that microglia surround a‐syn aggregates and when activated can cause increased extracellular superoxide, inflammatory cytokines, and selective loss of dopaminergic neurons.Previous studies showed varying total salivary α‐syn levels in PD patients compared to controls. Several studies have shown significantly lower total salivary α‐syn levels in PD patients compared to controls.2This systematic review and meta‐analysis are reported according to the PRISMA  following the PRISMA checklist and flow diagram for manuscript format development.Study inclusion and exclusion criteria:Study type(s): Prospective or retrospective studies published in any language were considered eligible to be included in this review.Study cases(s): Subjects with PD of any age, gender, or nationality whose saliva was evaluated using any available techniques were eligible.Study control(s): Subjects of any age, gender, or nationality without PD and other diseases whose saliva was evaluated using any available techniques were eligible.Objective outcome(s): Studies should at least compare total salivary alpha‐synuclein between cases and controls. Additional outcomes included but not mandatory were (1) oligomeric salivary alpha‐synuclein (2) ratio between oligomeric to total salivary alpha‐synuclein.The inclusion criteria were as follows:‐ Study result (s): Studies providing adequate data for calculations of mean difference of salivary alpha‐synuclein between cases and control and its 95% confidence interval were included.Study with insufficient information.Animal studies.Review articles, case reports/series, one‐arm clinical trials, conference abstractsStudies not reporting our primary outcome.The exclusion criteria were as follows:2.1PubMed, EMBASE, Google Scholar, and CNKI databases were searched for any language literature from January 2010 to August 2021. Boolean logic was used for conducting a database search, and Boolean search operators "AND" and "OR" were used to link search terms. Search strategy for PubMed search was as follows: ("Parkinson Disease"[MeSH Terms] OR "Parkinsonian Disorders"[MeSH Terms]) AND ) OR  OR "alpha‐Synuclein"[All Fields]))). Search strategy for EMBASE was as made with the help of emtree terms. The detailed search strategy is given in the supplementary file, Appendix 2.2Two independent investigators (SK and AB) performed a literature search from databases and additional sources. All the results were exported into the reference manager software, EndNote X7 . The studies were screened by abstract, and titles and duplicates were removed. Two investigators shortlisted articles after applying the inclusion and exclusion criteria. The third author (RO) came into play in case of any disagreements. An overall evaluation for potential overlap of the population was conducted based on authorship, hospital setting, and recruitment period. In cases of overlap, higher‐quality studies or larger sample sizes were included.2.3Two independent investigators (SK and AB) extracted data in an excel spreadsheet (Microsoft Corp.) using a standardized data extraction form. Results were compiled to complete the following fields: Author, year of publication, study site, study design, number of patients (PD and controls), measurement method, the mean age of patients and controls, the sex ratio of patients and controls, and the disease duration. The mean total salivary alpha‐synuclein among PD and controls was extracted. Data from other outcomes like oligomeric salivary alpha‐synuclein and ratio of oligomeric to total salivary alpha‐synuclein were also extracted among PD patients and healthy controls. A third reviewer (RO) was consulted to resolve inconsistencies when consensus was not reached. If the required data were missing, not reported in the paper, or reported in an unusual form, the corresponding authors of the respective papers were contacted via email for clarification. Supplementary Material associated with the main paper was also explored in such cases.2.4http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp) was used for the quality assessment of each study and described under three headings: selection,Two investigators (SK and AB) evaluated the quality of included studies in a consensus procedure. The Newcastle‐Ottawa Scale . The pooled mean differences of salivary alpha‐synuclein  between PD patients and healthy controls were evaluated using Standard Mean Difference (Hedges' g) with 95% CI. For those studies reporting median, range, and interquartile range, mean and SD were calculated.2.6P‐value of <0.05 was considered statistically significant.Sensitivity analysis was performed by sequentially omitting one study at a time to check the robustness of the analysis. The publication bias was assessed by Begg's test for small‐study effect size and shown in a funnel plot of standard error and effect size. A 33.1In total, 230 articles were identified after a thorough database search published from 2010 to 2021. Forty studies were removed as duplicates, and titles and abstracts screened 190. Out of the remaining 45 studies, 32 were excluded. After excluding duplicates and those not meeting inclusion criteria, 13 studies were reviewed for data collection.3.2In 13 studies, the sample of PD patients ranged from 20 to 201. The sex ratio  of PD patients ranged from 25% to 93.55% and the mean age ranged from 59.62 to 69.01 years. The duration of disease ranged from 3.8 to 9.9 years, while among healthy controls, the sample ranged from 15 to 198. The sex ratio  of controls ranged from 11.11% to 150% and their mean age ranged from 58 to 68.3 years.Likewise, measurement methods varied among different studies, including ELISA, Luminex, and others . Twelve out of 13 studies described the total salivary alpha‐synuclein among PD and controls, while one study had unclear data.3.3The quality assessment done for observational studies by the NOS scale showed the scores ranged from 6 to 8. Appendix . All the3.4p‐value = <0.001). A random‐effect model was used that showed significant heterogeneity  . A random‐effect model was used that showed significant heterogeneity   = 2.88, 95% CI: 0.59–5.16, 3.6p‐value = 0.01). A random‐effect model was used that showed significant heterogeneity   while not significant for the country of study (p = 0.089), methods of measurement (p = 0.055) and sex ratio (p = 0.555).To explore the cause of heterogeneity, subgroup analysis and meta‐regression were done comparing mean total salivary alpha‐synuclein among PD and healthy controls on various subheadings based on country of study, measurement methods, sex ratio, and disease duration. The subgroup analysis is described in Table p = 0.323), methods of measurement (p = 0.076), sex ratio (p = 0.459), and disease duration (p = 0.899) did not significantly affect effect sizes of mean differences among PD and healthy controls  .4This systematic review and meta‐analysis consisted of a total of 13 studies assessing the association of salivary alpha‐synuclein levels and Parkinson's disease. A previous systematic review by Bougea et al. comprising eight studies found that the diagnostic performance of the salivary synuclein was not robust enough to support the diagnosis of Parkinson's disease.It is well known that alpha‐synuclein makes a significant part of the protein content of LB associated with Parkinson's disease, and the aggregates of higher molecular weight causing cellular toxicity drive the disease process.In our meta‐analysis, total salivary alpha‐synuclein levels were significantly lower in PD than controls. However, this finding was inconsistent with many studies included in the analysis.The oligomeric and oligo to total salivary alpha‐synuclein levels showed significant increments in PD vs controls in accord with the individual studies while total α‐syn levels were lower in PD patients with respect to controls.Kang et al. showed a decrease in salivary alpha‐synuclein with the age of PD patients. The cause behind this may be due to undetectable epitome masked in aggregates.CSF, blood, nerve plexus, gut mucosa, and skin biopsy have been tested for alpha‐synuclein levels in search of potential biomarkers. Although CSF a‐syn levels produce the most consistent results, it is invasive. It may not be feasible to monitor long‐term progression and challenging to implement in a center with less experience. Skin biopsy, gut mucosa, and nerve plexus require an invasive procedure and have produced inconsistent results. Blood is easily accessible, but its level in blood is influenced by the degree of hemolysis and hence may not be suitable for diagnostic purposes.Early diagnosis can also unlock the possibility of advancement of new therapeutic interventions for the treatment of PD at an early stage.4.1This meta‐analysis includes data from 12 studies to show the pooled mean differences of salivary α‐syn levels among PD and controls. The findings of the present study have significant clinical and research implications. There were no language barriers, so studies with different ethnicity were included. We did subgroup analyses and meta‐regression to find the cause of heterogeneity.There are several limitations of our study. The studies included in our systematic review and meta‐analysis included PD patients at different levels of severity. There are great varieties among studies selected for this article causing high‐level heterogeneity, which might be due to the coexistence of various variables like α‐syn species , assays (ELISA vs Luminex), disease stage, genetic status, and patient groups. The diagnostic accuracy of salivary alpha‐synuclein is not described in our study. Similarly, there is no clear gold standard protocol for saliva collecting procedure, and microbiome composition may be influenced by the type of saliva collected (stimulated or unstimulated), questioning the conclusion based on biomarkers.Further, there is significant variation among studies regarding disease duration and α‐syn levels. Hence, its utility in monitoring disease progression cannot be established now. It is imperative that future studies employ uniform testing methods, and include patients with stringent inclusion criteria and at the same stage or duration of PD diagnosis.5Our systematic review and meta‐analysis found that salivary alpha‐synuclein parameters  were significantly different between PD patients and controls, suggesting usefulness as a simple, easy to use, cost‐effective, and reliable diagnostic biomarker for PD and its progression. Further studies, preferably with a larger sample size and multi‐ethnic, uniform diagnostic assay, and disease severity are warranted. These factors may help us evaluate the utility of measuring salivary alpha‐synuclein in diagnosing PD and monitoring its progression along with differentiation from other neurodegenerative disorders.The authors declare no conflicts of interest.SK and RO designed the study. SK and AB carried out the literature search, review, and selection. SK carried out the statistical analysis. SK, AB, and SPJ drafted the manuscript. RR, JKY, and RO were critically revising the manuscript for important intellectual content. All authors read and approved the final manuscript.Appendix S1‐S3Click here for additional data file.


More participants experienced adverse events (AEs) after solriamfetol 900 versus 300 mg (70% vs 29%); none were serious , and there were no deaths. Common AEs were nausea, dizziness, and palpitations. Neither solriamfetol dose resulted in QTcF prolongation > 10 milliseconds.Solriamfetol, a dopamine and norepinephrine reuptake inhibitor, is approved  to treat excessive daytime sleepiness associated with narcolepsy (75‐150 mg/day) or obstructive sleep apnea (37.5‐150 mg/day). A thorough QT/QTc study assessed solriamfetol effects on QT interval . This randomized, double‐blind, placebo‐ and positive‐controlled, 4‐period crossover study compared single doses of 300 and 900 mg solriamfetol, 400 mg moxifloxacin, and placebo in healthy adults. Placebo‐ and predose‐adjusted mean differences in QTcF  were analyzed, and solriamfetol pharmacokinetics were characterized. Fifty‐five participants completed all periods. Upper bounds of 2‐sided 90% confidence intervals (CIs) for ddQTcF for both solriamfetol doses were <10 milliseconds at all postdose time points. Assay sensitivity was demonstrated with moxifloxacin; lower bounds of 2‐sided 90%CIs for ddQTcF > 5 milliseconds at 1, 2, and 3 hours postdose. There were no QTcF increases > 60 milliseconds or QTcF values > 480 milliseconds at either solriamfetol dose. Solriamfetol median t Solriamfetol is a dopamine and norepinephrine reuptake inhibitorThe safety and efficacy of solriamfetol  in reducing EDS in patients with narcolepsy or OSA have been established in phase 3 clinical studies, including 6‐ and 12‐week randomized, double‐blind, placebo‐controlled studies and a 1‐year open‐label extension study.In vitro and in vivo nonclinical safety pharmacology studies have indicated minimal effects of solriamfetol on assessments of cardiovascular function. Specifically, solriamfetol at concentrations up to 10 µM  did not reduce rapid potassium current in the human ether‐a‐go‐go‐related gene (hERG) assay, had no notable effects on cardiac contractility in isolated guinea pig atria, and had no relevant effects on electrophysiological parameters or early after‐depolarizations in isolated rabbit Purkinje fibers. Notably, solriamfetol did not result in QT interval corrected for heart rate (QTc) prolongation in anesthetized rats, guinea pigs, or dogs or in conscious, unrestrained telemeterized beagles (data on file).To better characterize the effect of solriamfetol on QT/QTc, a thorough QT/QTc study was conducted. The primary objective of this study was to assess the effect of solriamfetol at doses of 300 and 900 mg  on QT interval corrected for heart rate (HR) using the Fridericia formula (QTcF) in healthy adult participants.Maryland), and the study was conducted in accordance with standard International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), U.S. Food and Drug Administration (FDA) regulatory requirements, Good Clinical Practice/ICH, the US Code of Federal Regulations pertaining to clinical studies, and the Declaration of Helsinki. Participants provided written informed consent before enrollment. The study was conducted from September 30, 2015, through October 21, 2015, at a single center in the United States .The protocol was approved by the institutional review board (IRB) for the study center  and placebo on QTcF prolongation. Solriamfetol pharmacokinetics (PK) were also characterized.The selection of solriamfetol doses used in this study  was based on guidance from the FDA and ICH, which recommend testing at substantial multiples of the anticipated maximum therapeutic exposure, if not precluded by considerations of safety or tolerability.2). Additional inclusion criteria included nonusers of nicotine‐containing products (≥3 months before first dose until the end of the study) and, for women of childbearing potential, use of a medically accepted method of birth control (≥2 months before first dose until ≥30 days after study completion). Main exclusion criteria included, but were not limited to, a medical history, physical findings, laboratory examination, or electrocardiogram (ECG) findings that might confound the results of the study or pose a risk to the participant; history or the presence of any disease or condition that could interfere with absorption, distribution, metabolism, or excretion of drugs; and participation in a prior study of solriamfetol.Eligible participants were healthy men and nonpregnant, nonlactating women (18‐55 years old) weighing at least 52 kg (men) or 45 kg (women) with normal body mass index , clinical and laboratory assessments were performed to ensure eligibility, and participants stayed for 2 days for each period. On the following day , data were collected including vital signs, as well as predose ECG data and blood samples for PK analysis. Following the collection of predose data, participants received a blinded dose of study medication; dosing occurred in the morning on each of the 4 dosing days, after an overnight fast of at least 8 hours.On each dosing day, participants received 3 identical‐looking capsules (each capsule contained placebo or a 300‐mg solriamfetol tablet) and 1 tablet (containing 400 mg moxifloxacin or placebo). Solriamfetol 300‐mg tablets, overencapsulated in opaque gelatin capsules and matching placebo capsules, were provided by the sponsor. Moxifloxacin neat film‐coated tablets  and matching placebo tablets were obtained by the pharmacy at the study site. ECG and blood samples were collected for 24 hours postdose. Following a second overnight stay and completion of the 24‐hour sampling time, participants were discharged. A 7‐day washout period between doses occurred after dosing in periods 1, 2, and 3. A safety follow‐up call was conducted approximately 7 ± 2 days after discharge from period 4 (or early study termination).For the assessment of QT/QTc intervals, Holter monitors  were used to collect 12‐lead ECGs from approximately 1 hour before dosing through 24 hours after dosing during each of the 4 treatment periods. QT/QTc interval following dosing was assessed from ECG data extracted from the Holter monitor at the following times: 1, 0.75, and 0.5 hours predose  and 1, 2, 3, 4, 6, 8, 12, and 24 hours postdose.At each scheduled time point, three 10‐second extractions were obtained from the Holter monitor within a 5‐minute time window ending at the nominal point. A single reader from the central cardiac laboratory  was used for the review of ECGs from a particular participant. The ECG recordings were measured and classified by software from AMPS, LLC, New York City, New York; all extracted ECG recordings were automatically measured by CalECG.2‐ethylenediaminetetraacetic acid tubes and kept on ice until the samples were centrifuged (within 30 minutes of collection) at ∼3000 revolutions per minute at 4°C for 10 minutes. The plasma was then pipetted into polypropylene tubes for freezing and storage at −20°C until analysis.Blood samples for PK measurements (4 mL) were collected at the same time points (except for the 1‐ and 0.75‐hour predose times) within a 5‐minute window after the nominal point at predose and 1, 2, 3, 4, 6, 8, 12, and 24 hours postdose. All blood samples were collected in labeled KAnalysis of plasma solriamfetol concentrations were performed by KCAS, LLC, Shawnee, Kansas, using a validated method. Solriamfetol and internal standard, R334898 (JZP‐110‐13C‐d2), were released from the human plasma by protein precipitation and subsequently derivatized using propionic anhydride to form their corresponding propionate products: solriamfetol propionate and R334898 propionate. After derivatization, the products were resolved chromatographically on a reverse phase using a mixture of 0.1% formic acid in water and 0.1% formic acid in methanol as the mobile phase with gradient elution using a 100 × 2.1 mm, 5‐micron particle Betasil C8 analytical column. Solriamfetol and R334898 were detected by monitoring the precursor and product ions (m/z 251.2 →190.2 for derivatized solriamfetol and m/z 254.2 → 193.2 for derivatized R334898) using an Applied Biosystems, Foster City, California, API4000 liquid chromatography‐tandem mass spectrometry unit. The lower limit of quantitation for analysis of solriamfetol in plasma was 8.42 ng/mL, with a range of 8.42‐4210 ng/mL. Inter‐ and intra‐assay relative standard deviation was below 6% for precision and below 2.7% for accuracy. PK blood samples collected during the moxifloxacin and placebo periods were stored. Because PK/pharmacodynamic (PD) modeling was only planned for solriamfetol, moxifloxacin and placebo samples were not analyzed.Safety and tolerability were assessed throughout the study. Assessments included adverse event (AE) monitoring, vital sign measurements, physical examinations, clinical laboratory tests , and the Columbia‐Suicide Severity Rating Scale (C‐SSRS). Single 12‐lead safety ECG recordings were obtained at screening, on each check‐in day, before dosing and approximately 2.5 hours after dosing on each dosing day, and on each discharge day and were reviewed by the investigator or qualified designee.The primary PD end points were predose‐adjusted mean difference between solriamfetol (300 and 900 mg) and placebo in QTcF (ddQTcF) and predose‐adjusted mean difference between moxifloxacin (400 mg) and placebo in QTcF (ddQTcF).Additional PD end points included the number and percentage of participants with any postdose absolute QTcF >450, >480, or >500 milliseconds; number and percentage of participants with predose‐adjusted mean change in QTcF (dQTcF) above a predefined threshold (QTcF increase from predose >30 or >60 milliseconds); number and percentage of participants with any postdose abnormal ECG morphology; mean absolute QTcF, QTcB , RR, and PR intervals, QRS duration, and derived ventricular HR for each interval; predose‐adjusted mean changes for ECG parameters ; and placebo‐ and predose‐adjusted mean difference in QTcB (ddQTcB).In addition, the relationship between placebo and predose‐adjusted mean differences in QTcF (ddQTcF) and plasma concentrations of solriamfetol was assessed.0‐t), AUC from time 0 to infinity (AUC0‐inf), maximum plasma concentration (Cmax), time to peak plasma concentration (tmax), apparent terminal elimination half‐life (t1/2), and apparent oral clearance (CL/F).Solriamfetol PK parameters were calculated by noncompartmental methods using Phoenix WinNonlin version 6.3, and included area under the plasma concentration‐versus‐time curve (AUC) from time 0 to time t of the last quantifiable concentration (AUCSafety variables included treatment‐emergent AEs (TEAEs), vital signs, clinical laboratory results , 12‐lead ECG findings, and C‐SSRS score.ECG parameters were analyzed using the ECG‐evaluable population, which included participants who had completed the placebo and at least 1 solriamfetol treatment period, had at least 1 evaluable postdose ECG recording for both these treatments, and had no major protocol deviation. Participants who were included in the ECG‐evaluable population but who had missing data for a particular end point were not included in the analysis for that end point. PK and safety data were analyzed using the safety population, which included all participants who received at least 1 dose of study drug.1/3.ECG data included HR and the following intervals: PR, RR, QRS, QT, QTcB, and QTcF. QTcF was the primary and a priori correction method because of the effects of solriamfetol on HR and was calculated as QTcF = QT/(RR)For all cardiodynamic ECG parameters, the average of the triplicate measurements was rounded to the nearest integer. The predose value for ECG parameters was defined as the mean of the 3 measurements recorded before day 1 dosing in each period . The placebo‐ and predose‐adjusted mean difference in QTcF intervals (ddQTcF) were calculated as the predose‐adjusted value for active treatment minus the predose‐adjusted value for placebo at each matching postdose time point.Analysis of the primary end point, ddQTcF, was performed using a repeated mixed‐effects analysis of covariance (ANCOVA) model that included treatment sequence, treatment period, sex, treatment, time, and time‐by‐treatment interaction as fixed effects and subject nested within sequence as a random effect; 2‐sided 90% confidence intervals (CIs) for ddQTcF were constructed at each point. Upper bounds of the 2‐sided 90%CIs could not exceed 10 milliseconds to conclude that this was a negative study according to ICH E14 guidance.t test. A total of 60 participants were planned in order to obtain data from approximately 52 participants completing all 4 periods per protocol.To determine assay sensitivity, the predose‐adjusted mean difference between moxifloxacin and placebo (ddQTcF) was evaluated using time trend plots and 2‐sided 90%CIs at each time point based on the mixed‐effects ANCOVA model. Assay sensitivity was tested at 1, 2, and 3 hours postdose (time points at which maximum QTc prolongation was likely to occur with moxifloxacin). Assay sensitivity was established if lower bounds of the corresponding 2‐sided 90%CI were >5 milliseconds. Hochberg adjustment was used to control for multiplicity at the 0.05 level of significance across comparisons at the 3 time points. With 52 participants who completed all 4 periods per protocol, there was at least 80% power to detect a predose‐adjusted mean difference of 5 milliseconds on the QTc interval between moxifloxacin and placebo. This calculation assumed a common standard deviation of 10 and a 1‐sided significance level of 0.05 using a PD measures of central tendency were summarized descriptively by treatment, including number and percentage of participants with QTcF intervals ≤450, >450 and ≤480, >480 and ≤500, and >500 milliseconds, and dQTcF intervals (predose adjusted) ≤30 milliseconds (including decrease from predose), >30 and ≤60 milliseconds, and >60 milliseconds.Correlation analyses were performed to evaluate the relationship between the placebo‐ and predose‐adjusted mean difference in QTcF (ddQTcF) and plasma concentrations of solriamfetol. Pearson correlation coefficients were calculated separately for each treatment.Solriamfetol plasma concentrations, PK parameters, and safety data were summarized descriptively. For the calculation of PK summary statistics, values that were below the limit of quantification (below 8.42 ng/mL) were treated as 0. AEs were summarized by treatment at onset.Of 114 potential participants screened, a total of 60 participants entered the study, were randomized, and received study drug; 15 participants were assigned to each of the 4 treatment sequences. All 60 enrolled participants received at least 1 dose of study drug and were included in the safety population. The total ECG‐evaluable population included 59 participants . A total of 57 participants completed the study; 2 participants discontinued because of AEs and 1 discontinued for personal reasons.Demographics and baseline characteristics were generally similar across treatment groups Table . The majThe mixed‐effects ANCOVA model analysis showed that the lower bounds of the 2‐sided 90%CIs for the difference in mean dQTcF between moxifloxacin and placebo (ddQTcF) were all >5 milliseconds at 1, 2, and 3 hours after dosing , the upper bounds of the 2‐sided 90%CI for the mean difference between the 300‐ or 900‐mg solriamfetol doses and placebo were <10 milliseconds at all postdose time points  was 1.3843 (1.9338). At a Cmax of 5290 ng/mL, following the 900‐mg dose, the estimated mean ddQTcF (upper 90% confidence bound) was 8.0274 (9.1173).Results of the ddQTcF‐concentration correlation analysis showed that the mean slope of the regression equation was 0.00189 milliseconds per ng/mL , and the mean AUC0‐inf was approximately 3.5‐fold greater  following the 900‐mg dose compared with the 300‐mg dose, indicating dose proportionality; mean t1/2 was similar for both doses . Mean CL/F values were similar at the 2 doses .Solriamfetol was rapidly absorbed, with median tTEAEs were reported by 46 (77%) of the 60 participants  increase from baseline at discharge (∼24 hours postdose) was observed after dosing with solriamfetol 900 mg (median changes in systolic blood pressure [SBP] and diastolic blood pressure [DBP] were ∼5 mm Hg), and a minimal increase was noted for solriamfetol 300 mg. Mean BP remained within normal range.In this study, neither dose (300 or 900 mg) of solriamfetol resulted in QTcF prolongation, as defined by the upper bound of a 2‐sided 90%CI for ddQTcF exceeding 10 milliseconds. In contrast, the lower bound of the 2‐sided 90%CI for QTcF following administration of moxifloxacin 400 mg was >5 milliseconds, establishing assay sensitivity for the study. Thus, the study met the criteria for a negative thorough QT study per ICH E14 guidance.max corresponding to either solriamfetol dose; thus, these results were consistent with the ddQTcF analysis.Results from QTcF categorical analyses were supportive of the ddQTcF end point. Specifically, there were no increases from baseline QTcF > 60 milliseconds nor any absolute QTcF values > 480 milliseconds in any participants at either dose of solriamfetol. Furthermore, no participant had an increase from baseline QTcF > 30 milliseconds following administration of 300 mg solriamfetol. In the correlation analysis of ddQTcF and plasma solriamfetol concentrations, the upper bounds of the 90%CI for ddQTcF were <10 milliseconds at the mean CThe QTcF findings in this study are consistent with previous phase 2 and 3 clinical studies, which included participants with narcolepsy or OSA, who may be more susceptible to arrhythmogenic effects because of their underlying disease compared with healthy populations. Although these studies did not systematically evaluate QTcF as an outcome as was done in the current study, clinical assessments were conducted based on vital signs, ECG, and reported AEs.Published QTc data for other wake‐promoting treatments are limited. Pooled data from 6 randomized, placebo‐controlled trials suggest that clinically meaningful ECG changes with modafinil are similar to those with placebo and suggest a lack of treatment‐emergent ECG abnormalities.max of 2 and 3 hours following oral administration of 300‐ and 900‐mg doses, respectively.The PK profile of solriamfetol in this study is consistent with what has previously been reported in healthy adults.max and 3.5‐fold greater AUC0‐inf were observed following the 900‐mg dose compared with the 300‐mg dose, indicating dose‐proportional PK. The mean half‐life of 5 to 6 hours was similar for the 300‐ and 900‐mg doses.An approximately 3‐fold higher solriamfetol CThe tolerability of solriamfetol at the 300‐mg dose was consistent with what has been observed in clinical efficacy studies.This thorough QT/QTc study demonstrated that single doses of solriamfetol at doses of 300 and 900 mg met the criteria for a negative thorough QT study per ICH E14 guidance. The PK and safety/tolerability profiles were consistent with what has been previously reported.K. Zomorodi, D. Chen, and L. Carter are employees of Jazz Pharmaceuticals, who in the course of their employment, have received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. L . Lee is a former employee of Jazz Pharmaceuticals, who in the course of his employment, has received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. D. Swearingen has nothing to disclose.This study was supported by Jazz Pharmaceuticals. Jazz Pharmaceuticals has worldwide development, manufacturing, and commercialization rights to solriamfetol, excluding certain jurisdictions in Asia. SK Biopharmaceuticals, the discoverer of the compound , maintains rights in 12 Asian markets, including Korea, China, and Japan.Study concept and design: Carter, Chen, Zomorodi.Acquisition of data: Swearingen, Zomorodi.Study investigator: Swearingen.Data analysis and interpretation: Carter, Chen, Zomorodi.Enrolled patients: Swearingen.Drafting of the manuscript: all authors.Critical revision of the article for important intellectual content: all authors.Under the direction of the authors, Sherri Jones, PharmD, and Jeannette Fee of Peloton Advantage, LLC, an OPEN Health company, provided medical writing and editorial support for this article, which was funded by Jazz Pharmaceuticals.All relevant data are provided within the article and supporting files.