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To investigate how a high risk for infant neurological impairment affects the quality of infant verbal interactions, and in particular properties of infant-directed speech, spontaneous interactions between 14 mothers and their 4.5-month-old infants at high risk for neurological disorders (7 female) were recorded and acoustically compared with those of 14 dyads with typically developing infants (8 female). Mothers of at-risk infants had proportionally less voicing, and the proportion of voicing decreased with increasing severity of the infants’ long-term outcome. Follow-up analysis based on manual annotation of phonation style revealed breathy phonation as more common toward infants with more severe long-term outcomes (N=7; 44.7% of speech) than controls (N=14; 22.0%; p=0.005) or at-risk infants with typical or mildly abnormal long-term outcomes (N=7; 16.5%; p=0.002). The results indicate that maternal phonation style during early dyadic interactions is affected by the infant’s neurological condition.
The Greek anti-Ottoman revolt in the 1820s brought increased suspicion among the empire’s ruling circles toward not only Greeks but non-Muslim subjects in general. This sparked government security measures in Istanbul, home to substantial Christian and Jewish populations. This article examines such measures intended to bring non-Muslim subjects under control, and the overall impact the Greek revolt had on the Ottoman approach to its subjects. It argues that the revolt catalyzed changes in the state’s attitude toward population surveillance and its treatment of non-Muslims. When the empire felt the need to bring non-Muslims under control, a major challenge was how to verify and vouch for the latter’s identity, since they deemed Muslim officials incapable of doing so. Thus, though they were suspicious of non-Muslims, they actively used the religious authorities of their communities to implement various security measures, including the creation of a population record and the introduction of internal passports. At the same time, religious authorities found it essential to demonstrate their and their community’s pro-Ottoman position by cooperating with the state in its efforts to find enemies within. Incorporation of non-Muslim religious authorities into imperial governance led to official recognition of the representatives of smaller non-Muslim groups, including Latin subjects, Armenian Catholics, and Jews. The result was a standardization of non-Muslim communities with officially recognized representatives before the government.
Esketamine (ESK) nasal spray and interventional therapies including electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) are indicated for patients with treatment resistant depression (TRD). Little is known about healthcare resource use and associated costs of Medicaid beneficiaries, a population with a high burden of mental health disorders, initiating ESK, ECT or TMS. This study aimed to bridge this gap in knowledge.
Methods
Medicaid-insured adults with evidence of TRD (≥2 unique antidepressants of adequate dose and duration) were selected from Merative™ MarketScan® Multi-State Medicaid Database (01/2016-06/2022). Based on therapy initiated on or after 03/05/2019 (ESK approval date for TRD), patients were classified into three cohorts: ESK, ECT, and TMS. Before treatment initiation (index date), patients had ≥12 months of continuous insurance eligibility (baseline period). Mental health (MH)-related resource use and payer costs (USD 2022) were reported per-patient-per-month (PPPM) during the follow-up period, which spanned the index date until the earliest continuous insurance eligibility or data end.
Results
ESK cohort included 151 patients (mean age: 40.6 years; female: 70.2%), ECT cohort included 198 patients (mean age: 43.0 years; female: 60.6%), and TMS cohort included 140 patients (mean age: 39.5 years; female: 65.0%).
During the follow-up period, the mean number of MH-related inpatient (IP) days trended lower in ESK cohort (0.09) relative to the ECT (3.72) and TMS (0.31) cohorts. Similarly, the mean number of MH-related emergency department (ED) visits trended lower in ESK cohort (0.07) relative to ECT (0.12) and TMS (0.26) cohorts. The mean number of MH-related outpatient (OP) visits in ESK cohort (4.83) trended higher than in ECT cohort (4.37) but lower than in TMS cohort (6.41). Mean MH-related acute care costs during the follow-up period trended lower in ESK cohort (IP: $76; ED: $29) relative to ECT (IP: $1,547; ED: $45) and TMS cohorts (IP: $238; ED: $123). Outpatient costs in ESK cohort ($1,632) exceeded OP costs in ECT ($1,023) and TMS ($1,051) cohorts.
Conclusion
In this descriptive analysis, a trend towards lower use and costs of acute MH-related care was observed after the initiation of ESK relative to the initiation of ECT and TMS. This finding should be interpreted with caution, given potential differences in patient profiles, clinical history and setting of administration.
Funding
Janssen Scientific Affairs, LLC. Analysis Group is a consulting company that has provided paid consulting services to Janssen Scientific Affairs, LLC, which funded the development and conduct of this study.
In an era characterised by information saturation and the rapid evolution of digital communication platforms, the study of persuasive language is undergoing profound developments. Bringing together cutting-edge research from a team of internationally acclaimed experts, this timely book examines the transformations occurring in the domain of persuasive language in contemporary society. It dissects the intricate web of manipulation, influence and deception, providing in-depth analyses of the potent mechanisms governing communication. Each chapter offers empirical insights from a range of different scholarly perspectives, including corpus linguistics, conversation analysis, forensic linguistics, pragmatics, discourse analysis, phonetics and human-robot interactions. It opens with a comprehensive introductory chapter, making the research accessible to readers without extensive background knowledge. Equipping readers with the tools to critically engage with the multifaceted dynamics of language and persuasion, this is an indispensable resource for anyone striving to fathom the evolving realm of persuasive language.
Attention-deficit/hyperactivity disorder (ADHD) remains underdiagnosed and undertreated in girls. One important contributor is the predominance of inattentive symptoms in girls relative to boys. Though less “visible,” inattentive symptoms represent a key driver of impairment, often persisting into adulthood. EndeavorRx (AKL-T01) is a game-based, FDA-authorized digital therapeutic directly targeting inattention. This analysis sought to examine potential sex differences in the efficacy of AKL-T01.
Methods
We conducted a secondary analysis of clinical outcomes by sex in 326 children and adolescents from two trials of AKL-T01 (n1 = 180 children; 30.6% female, M age = 9.71; n2 = 146 adolescents; 41.1% female, M age = 14.34). All participants had high inattention per a baseline score ≤ -1.8 on the Test of Variables of Attention (TOVA), a computerized, FDA-cleared continuous performance task objectively measuring attention. Participants used AKL-T01 for 25 minutes/day over 4 weeks. Primary outcomes included change in attention on the TOVA Attention Comparison Score (ACS) and sub-metrics, and change in symptoms on clinician-rated ADHD Rating Scale (ADHD-RS). To evaluate study hypotheses, we conducted a series of t-tests of TOVA and ADHD-RS change scores by sex.
Results
Across the pooled sample, girls using AKL-T01 demonstrated significantly greater improvements in attention on the TOVA ACS (MΔ = 2.44) compared to boys (MΔ = 1.32; t[211.77]) = 2.62, d = .31, p = .009), as well as TOVA reaction time standard score (girls’ MΔ = 13.22; boys’ MΔ = 3.54; t[229.12] = 3.93, d = .46, p <.001). We did not observe sex differences in the 2 other TOVA sub-metrics, nor in ADHD-RS (ps >.05). There were sex differences in compliance (t[207.99] = 2.17, d = .26, p = .031), with girls completing more sessions on average (M = 90.22) compared to boys (M = 80.19).
Conclusions
Results suggest that AKL-T01 may be associated with particularly strong improvements to attentional functioning in girls relative to boys. That there were no significant sex differences in ADHD symptom change over the course of treatment in either sex underscores the specificity of these effects to inattention processes rather than broad ADHD symptoms. Limitations include categorization based on binary sex, which may not capture nuances of gender identity.
Pharmacogenomic (PGx) testing identifies individual genetic variation that may inform medication treatment. Lack of awareness and education may be barriers to implementing routine PGx testing. To characterize current PGx testing utilization and educational needs we conducted a survey of various provider types.
Methods
Healthcare providers in the primary care setting were targeted between November 2022 and February 2023 via the Medscape Members paid market research program. The survey included 5 demographic, 5 multiple-choice, and 4 multi-component five-point Likert scale questions to assess PGx sentiments, use, and education in mental health (e.g., depression) and primary care (e.g., cardiovascular disease) conditions. Responses were descriptively compared.
Results
Of 305 U.S. provider respondents [40% nurse practitioners (NPs), 33% frontline MDs/DOs, 3% physician assistants (PAs), 24% other], most indicated that they “don’t use” (44-49%) or “have never heard of” (19-20%) PGx testing for mental health conditions. The most helpful sources to learn about PGx testing were accredited CE/CME activities (55-61%) and peer-reviewed publications (57-59%). Most NPs/PAs preferred webinars (62%) or online learning portal (57%) formats. MDs/DOs had no preference for webinars or learning portals over conferences, written materials, or academic presentations (45-47%). NPs/PAs were more interested in learning about PGx testing than MDs/DOs (4.29/5 vs. 3.96/5 average score).
Conclusions
These data reveal awareness level and desired learning opportunities for PGx testing between types of healthcare providers. Education should be tailored to meet providers’ preferred learning formats and information sources, such as offering CE/CME through an online learning portal.
In this paper, I analyze an intricate morphological pattern in Murrinhpatha which involves reordering of the dual marker ngintha and an alternation in the form of its adjacent morpheme. I will argue that the pattern strongly suggests an analysis in Stratal Optimality Theory: first, phonological correlates of morphological structure provide evidence for cyclic domains within the word. Second, the phenomenon can be derived using independently motivated morphological constraints, thus supporting the idea that morphology is an independent module of grammar with different optimization mechanisms, but the same stratal split as phonology. The cyclic architecture of the word provides a straightforward explanation for the placement of the dual marker and the resulting allomorphy of the classifier stem without resorting to ad hoc mechanisms such as position classes. Furthermore, the cyclic structure neatly accounts for multiple exponence of [dual] through the daucal (dual/paucal) classifier stem and ngintha. My analysis suggests that this overexponence results from the blocking of ngintha in the first cycle and the selection of the featurally more specific daucal stem. However, ngintha is not strictly bounded to the first cycle, and its realization is delayed until the second cycle.
This review aims to highlight the relative importance of cardiovascular disease (CVD) lifestyle-associated risk factors among individuals with inflammatory bowel disease (IBD) and examine the effectiveness of lifestyle interventions to improve these CVD risk factors. Adults with IBD are at higher risk of CVD due to systemic and gut inflammation. Besides that, tobacco smoking, dyslipidaemia, hypertension, obesity, physical inactivity, and poor diet can also increase CVD risk. Typical IBD behavioural modification including food avoidance and reduced physical activity, as well as frequent corticosteroid use can further increase CVD risk. We reviewed seven studies and found that there is insufficient evidence to conclude the effects of diet and/or physical activity interventions on CVD risk outcomes among populations with IBD. However, the limited findings suggest that people with IBD can adhere to a healthy diet or Mediterranean diet (for which there is most evidence) and safely participate in moderately intense aerobic and resistance training to potentially improve anthropometric risk factors. This review highlights the need for more robust controlled trials with larger sample sizes to assess and confirm the effects of lifestyle interventions to mitigate modifiable CVD risk factors among the IBD population.
For $M,N,m\in \mathbb {N}$ with $M\geq 2, N\geq 1$ and $m \geq 2$, we define two families of sequences, $\mathcal {B}_{M,N}$ and $\mathcal {B}_{M,N,m}$. The nth term of $\mathcal {B}_{M,N}$ is obtained by expressing n in base M and recombining those digits in base N. The nth term of $\mathcal {B}_{M,N,m}$ is defined by $\mathcal {B}_{M,N,m}(n):=\mathcal {B}_{M,N}(n) \; (\textrm {mod}\;m)$. The special case $\mathcal {B}_{M,1,m}$, where $N=1$, yields the digit sum sequence $\mathbf {t}_{M,m}$ in base M mod m. We prove that $\mathcal {B}_{M,N}$ is the fixed point of a morphism $\mu _{M,N}$ at letter $0$, similar to a property of $\mathbf {t}_{M,m}$. Additionally, we show that $\mathcal {B}_{M,N,m}$ contains arbitrarily long palindromes if and only if $m=2$, mirroring the behaviour of the digit sum sequence. When $m\geq M$ and N, m are coprime, we establish that $\mathcal {B}_{M,N,m}$ contains no overlaps.
Viloxazine ER (extended-release capsules; Qelbree®) is a nonstimulant medication, FDA-approved for ADHD in children (≥6 years) and adults. Efficacy and safety for children and adolescents were evaluated in one phase 2 [NCT02633527]and four phase 3 [NCT03247517, NCT03247556, NCT03247530, and NCT03247543], double-blind (DB), placebo-controlled trials that fed into a long-term, open-label extension (OLE) trial [NCT02736656]. Here we report the findings from this OLE trial.
Methods
Participants completing the DB trials were eligible for the OLE. Viloxazine ER was initiated at 100 mg/day (children) or 200 mg/day (adolescents) and adjusted (if needed) over a 12-week Dose-Optimization Period (up to 400 mg/day [children] or 600 mg/day [adolescents]). Maintenance treatment then continued up to 72 months. Safety assessments included adverse events (AEs), clinical laboratory tests, vital signs, ECG (12-lead), and the Columbia Suicide Severity Rating Scale (C-SSRS). Efficacy assessments included the ADHD Rating Scale, 4th (Phase 2) or 5th (Phase 3) Edition (ADHD-RS-IV/5), and the Clinical Global Impression-Improvement (CGI-I) scale. Efficacy was assessed relative to DB baseline at study visits ˜ 3 months apart. Two response measures, 50% improvement in ADHD-RS-IV/5 Total score and CGI-I score of 1-2, were also evaluated.
Results
1100 individuals (646 children; 454 adolescents; 66.5% male/33.5% female) received treatment. Median (range) exposure to viloxazine ER was 260 (1 to 1896) days. AEs were reported by 57.3% participants, most commonly (≥5%) nasopharyngitis (9.7%), somnolence (9.5%), headache (8.9%) decreased appetite (6.0%), and fatigue (5.7%). AEs were mostly mild or moderate in severity (3.9% reported any severe AE); AEs led to viloxazine ER discontinuation for 8.2%. The mean (SD) changes from DB baseline in ADHD-RS IV/5 Total score were -17.0 (14.18) (viloxazine ER) and -11.2 (13.19) (placebo) at the last DB study visit, 24.3 (11.96) at OLE Month 3, and 22.4 (13.62) at participants’ last OLE study visit. ADHD-RS-IV/5 and CGI-I responder rates each exceeded 65% at all OLE visits following Dose-Optimization.
Conclusions
The safety and efficacy of viloxazine ER were maintained with long-term use in children and adolescents with ADHD. No new safety concerns emerged, and efficacy results suggested potential for continued improvement over that seen during DB treatment.
IDgenetix is an advanced multi-gene pharmacogenomic (PGx) test that incorporates drug-gene interactions, drug-drug interactions, and lifestyle factors to guide medication management for patients diagnosed with major depressive disorder (MDD), anxiety, or other mental illnesses. In a previously published randomized controlled trial (RCT), IDgenetix significantly improved patient response and remission rates (Bradley et al., 2018). In this analysis, we aimed to compare the clinical outcome results from the RCT with real-world evidence from an open-label study (Cao et al., 2023).
Methods
Subjects with moderate to severe MDD at baseline per their HAM-D17 or PHQ-9 scores were included in the analysis for the RCT (n=261) and real-world data (n=242). In both studies, 8-week response and remission rates were analyzed for patients using IDgenetix-guided medication management (Guided) compared to patients receiving standard of care (Unguided).
Results
Patient response and remission rates strongly aligned between both studies. Response rates for the IDgenetix-guided participants in the RCT were 49% compared to 58% in the real-world data. Remission rates in the Guided group were 31% in both the RCT and real-world study compared to 22% and 19%, respectively, for participants in the Unguided group.
Conclusions
Comparing the clinical outcome results from the RCT with real-world data demonstrated the consistent impact of IDgenetix on patient response and remission rates. This study provides robust evidence-based research that supports the clinical use of IDgenetix to guide medication management in patients with MDD.
Tardive dyskinesia (TD) is associated with antipsychotic (AP) use and management includes antipsychotic (AP) dose modification/discontinuation, often leaving underlying psychiatric conditions undertreated. Deutetrabenazine (DTBZ) is a vesicular monoamine transporter type 2 inhibitor (VMAT2i) approved to treat TD and Huntington disease– associated chorea. AP and VMAT2i treatment patterns post-TD diagnosis are unclear.
Methods
Patients aged ≥18 years, newly diagnosed with TD (July 2019– June 2022), with ≥1 AP and no VMAT2i claims pre-index were identified from the Symphony Health Solutions Integrated Dataverse (medical, hospital, and prescription claims across all US payer types). Patients were grouped into DTBZ (≥1 DTBZ claim within ≤6 months post-diagnosis) and non-VMAT2i groups, and further by stable DTBZ dose (for ≥60 days). The index date was the first DTBZ claim (DTBZ group) or the difference between TD diagnosis and first DTBZ claim (of the matched patient) added to TD diagnosis (non-VMAT2i group).
Results
Among 18,375 patients meeting inclusion criteria, 587 (3%) received DTBZ (292 stable-dose DTBZ), 676 (4%) received a different VMAT2i, and 17,112 (93%) had no VMAT2i claims. Among propensity score-matched patients with ≥1 AP claim pre- and post-index (326 DTBZ, 627 non-VMAT2i), pre-index mean AP proportions of days covered (PDCs) were similar between DTBZ (86%), stable-dose DTBZ (86%), and non-VMAT2i (83%) groups. Mean PDCs decreased post-index for DTBZ (86% to 85%) and non-VMAT2i (83% to 81%) groups, but increased for the stable-dose DTBZ group (86% to 88%). While these changes were small, post-index mean PDCs were significantly greater (versus non-VMAT2i) in the DTBZ (5% difference; P=.030) and stable-dose DTBZ (9%; P=.001) groups. Similar proportions of patients in the DTBZ (20%) and non-VMAT2i (20%) groups discontinued APs (ie, no AP claims within ≤6 months post-index). Proportions of patients with AP restarts (7%– 8%) and dose decreases (13%– 17%) were also similar between DTBZ, stable-dose DTBZ, and non-VMAT2i groups. Proportions of patients (16%– 18%) with AP dose increases were similar between DTBZ and non-VMAT2i groups, but significantly greater in the stable-dose DTBZ group (21%) vs non-VAMT2i (P=.02).
Conclusions
AP adherence was significantly, though not substantially, greater for DTBZ versus non-VMAT2i groups. These results suggest that DTBZ, when titrated to a stable/optimal dose, allows flexibility in treating underlying psychiatric conditions.
The development of inhibitory control (IC) and working memory (WM) in preschool is linked to a multitude of cognitive, emotional, and social outcomes, including elementary school adjustment. Furthermore, there are both cognitive and socioemotional domains of IC and it is unclear if both are related to these outcomes in the same manner. Using a family study design, the present investigation examined preschoolers’ IC, WM and externalizing behavior problems, maternal depression and anxiety measured when the children were in preschool, and elementary school externalizing behaviors and child and family functioning. Families with two children between 2.5 and 5.5 years of age (n = 198; mean age = 3.88, SD = 1.04) completed online surveys and laboratory visits, as well as another online survey after the children entered elementary school. Both cognitive and emotional domains of preschool IC significantly predicted the externalizing and functioning aspects of adjustment in elementary school (but WM did not predict either). In addition, child age predicted functioning in elementary school, and maternal depression predicted externalizing in elementary school. These longitudinal results indicate that supporting both cognitive and emotional aspects of preschool IC can benefit adjustment in elementary school.
Craig Chepke, MD: Excel Psychiatric Associates, Huntersville, NC, and Atrium Health, Charlotte, NC; Andrew J. Cutler, MD: SUNY Upstate Medical University, and Neuroscience Education Institute, Syracuse, NY; Samantha Floam, DMD: Axsome Therapeutics, New York, NY; Gregory, Parks, PhD: Axsome Therapeutics, New York, NY; Russell Rosenberg, PhD: Neurotrials Research, Atlanta, GA
Introduction
Solriamfetol (Sunosi®), a dopamine/norepinephrine reuptake inhibitor that has been shown to activate TAAR1, is approved (US and EU) to treat excessive daytime sleepiness (EDS) in adults with narcolepsy (75-150 mg/day) or obstructive sleep apnea (OSA) (37.5-150 mg/day).Effect size, number needed to treat (NNT) and number needed to harm (NNH) are statistical representations of efficacy and tolerability that clinicians may find helpful in guiding treatment decisions. This analysis characterized these statistical parameters from two registrational studies.
Methods
Post-hoc analysis of data from two phase 3 studies in adults with excessive daytime sleepiness associated with narcolepsy (TONES 2) or obstructive sleep apnea (TONES 3). Effect size compared to placebo, NNT, and NNH were calculated based on previously published endpoints, post-hoc analyses, and adverse events.
Results
On the maintenance of wakefulness test (MWT), effect size compared to placebo (Cohen’s d) was 0.29, 0.82, and 1.13 for 75mg, 150mg, and 300mg doses of solriamfetol in TONES 2 and 0.46, 0.89,1.08, and 1.28 for 37.5mg, 75mg, 150mg, and 300mg, respectively. On the Epworth sleepiness scale (ESS), d was 0.47, 0.80, and 1.02 for 75mg, 150mg, and 300mg doses in TONES 2, and 0.42, 0.37, 0.99, and 1.04 for 37.5mg, 75mg, 150mg, and 300mg doses in TONES 3. NNT for patients achieving an ESS ≤10 was 7, 5, and 3 for 75mg, 150mg, and 300mg doses in TONES 2 and 8, 6, 4, and 3 for 37.5mg, 75mg, 150mg, and 300mg doses in TONES 3. On the patient global impression of change (PGIc), NNT was 4, 3, and 3 for 75mg,150mg, and 300mg doses in TONES 2 and 16, 5, 3, and 3 for 37.5, 75mg, 150mg, and 300mg in TONES 3. Similar NNT were found for the clinician global impression of change (CGIc) as for the PGIc. In both TONES 2 and TONES 3, NNH pooled across doses for adverse events occurring in at least 5% of patients and greater than placebo were all >10, with the exception for headache in TONES 2 (NNH=6).
Conclusion
This post-hoc analysis demonstrates favorable effect size, NNT and NNH values for solriamfetol in the treatment of EDS associated with narcolepsy and OSA.
Pharmacogenetic testing is becoming more common, especially to provide guidance for psychiatric medications. Over 17 psychotropic medications currently have a Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline. Several clinical trials have described PGx testing in specific patient populations, but various exclusion criteria create cohorts that may not represent real-world populations. Given the overall undefined characteristics of a real-world population utilizing commercial PGx testing, the clinical presentation of 15,198 patients that used a commercial PGx laboratory (Genomind) from October 15, 2018 through April 11, 2023 was assessed. These 15,198 patients include those whose provider conducted a clinical consultation with a Genomind psychopharmacologist, regardless of ICD diagnosis on the requisition form. Data were extracted from de-identified consult notes entered by the psychopharmacologist. Consultants made a total symptom severity assessment based on CGI-S (Clinician Global Impression Severity) criteria. Most patients were described as mildly (15%), moderately (59%), or markedly ill (21%). The most common presenting symptoms identified in the cohort were “Anxious” (61.6%), “Depressed” (61.1%), “Inattentive” (37.8%) and “Hyperactive” (11.4%). The most common co-occurring symptoms in patients with a depressive presentation were “Anxious” (68.1%), “Inattentive” (16.0%), “Manic/Hypomanic” (11.1%), “Insomnia” (9.8%) and “Irritable/Angry” (7.4%). The most common co-occurring symptoms in patients presenting with anxiety were “Depressed” (67.6%), “Inattentive” (20.9%), “Panic” (11.5%), “Worry/Rumination” (11.2%) and “Hyperactive” (11.1%). This analysis suggests that PGx testing is commonly being utilized in patients with symptoms of anxiety, mood lability and inattentiveness. Future PGx research should prioritize the selection of patients with these symptoms to generate evidence that matches the real-world users of commercial PGx services.
Trioctahedral phyllosilicate minerals are widely distributed on the Earth’s surface, especially in soil. The mineral–water interfacial reaction of lizardite, chlorite and talc, with various structural properties (tetrahedral sheet, octahedral sheet, 1:1-type and 2:1-type interlayer domain/two-dimensional structural units), was carried out in sulfuric acid solution (1 mol L–1). The mineral samples were characterized by powder X-ray diffraction, Fourier-transform infrared spectroscopy, scanning and transmission electron microscopy and inductively coupled plasma mass spectrometry. The dissolution concentration, dissolution rate, dissolution rules and structural changes of the components during the dissolution processes of the various two-dimensional structural units were studied. The results show that the dissolution concentrations of Si and Mg in the sulfuric acid solution decrease in the following order: chlorite > lizardite > talc and lizardite > chlorite > talc. The dissolution rates of Si in chlorite and Mg in lizardite are the greatest, while talc is the most stable compared with lizardite and chlorite. With increasing interfacial reaction time and the dissolution of the ionic components of the minerals, the structure of lizardite is gradually destroyed; the structural destruction of chlorite is more obvious during the early stages of the reaction; and the structure of talc does not significantly change over the course of the entire reaction. By analysing the microtopography of the minerals, it was found that the structural failure of lizardite occurred from the surface to the interior. Chlorite had more structural defects and showed collapse of the layered structure during structural failure. The surface layer of talc decomposed by corrosion into a small lamellae structure attached to the surface, but there was no obvious structural change similar to those of lizardite and chlorite. The relationship between the evolution of composition and structure during the mineral–water interfacial reaction process with the two-dimensional structure layer type provides the mineralogical basis for studying the coupling mechanism of the migration and transformation of materials in key regions of the Earth.
In ESCAPE-TRD (NCT04338321), a randomized, open-label, rater-blinded, long-term, phase 3b trial, augmentation with esketamine nasal spray (ESK) demonstrated increased probability of achieving meaningful clinical benefit versus quetiapine extended release (QUE XR) in patients (pts) with treatment-resistant depression (TRD). This subgroup analysis of ESCAPE-TRD evaluated the incidence, duration, and impact of treatment-emergent adverse events (TEAEs) on treatment discontinuation in adults with TRD treated with ESK or QUE XR according to US prescribing information.
Methods
Pts aged 18-64 years were randomly assigned to receive flexibly dosed ESK (56 or 84 mg) or QUE XR (150-300 mg), both consistent with US label dosing and in combination with an ongoing oral antidepressant. The incidence and duration of the most commonly occurring TEAEs, as well as the most common TEAEs leading to treatment discontinuation, were summarized descriptively. All randomly assigned participants receiving ≥1 dose of study drug were included in the safety analyses.
Results
Among the 636 pts included in the subgroup analysis, 316 and 320 were randomly assigned to ESK and QUE XR, respectively; 314 and 316 were included in the safety population. In the combined acute and maintenance phases, TEAEs occurred in 92.0% of pts in the ESK group and 78.5% of pts in the QUE XR group. The most commonly reported TEAEs with ESK or QUE XR in the combined acute and maintenance phases were dizziness (47.1% and 7.9%, respectively), headache (25.5% and 13.0%, respectively), somnolence (15.0% and 23.4%, respectively), and nausea (29.9% and 3.2%, respectively). Across all TEAE events reported in >5% of pts in either arm, 91.8% (5831 of 6351) resolved within 1 day in the ESK arm compared to 11.6% (90 of 776) with QUE XR. For specific TEAE events of clinical interest for ESK, same-day resolution rates for increased blood pressure, sedation, and dissociation in the ESK group were 93.5% (116 of 124), 96.2% (127 of 132), and 99.6% (740 of 743), respectively. The majority of TEAEs of clinical interest in the ESK group that occurred on the same day of dosing resolved within the first 2 hours after dosing. For the most frequently reported TEAEs with QUE XR, same-day resolution rates for somnolence, headache, and fatigue were 7.8% (8 of 103), 49.2% (29 of 59), and 9.5% (4 of 42), respectively. Fewer pts treated with ESK discontinued treatment due to TEAEs compared to QUE XR (4.4% versus 10.6%).
Conclusions
Safety data from this subgroup analysis were consistent with the overall study population as well as the known tolerability profile of each treatment. TEAEs were reported at higher incidence with ESK than with QUE XR; however, the majority of TEAEs occurring with ESK were transient in nature and did not result in a higher rate of treatment discontinuation compared to QUE XR.