Use of video-recordings of site-based interviews for quality assurance in a study of subjects with schizophrenia and persistent negative symptoms.

Site-independent ratings derived from audio-digital recordings of site-based interviews are often used for quality assurance monitoring to affirm ratings reliability in CNS clinical trials. The present study of subjects with schizophrenia and persistent negative symptoms used video instead of audio recordings of site-based interviews and thereby facilitated visual observation of the subject by the remote rater. "Paired" site-independent scores of the Positive and Negative Syndrome Scale (PANSS) and Brief Negative Symptom Scale (BNSS) were obtained from video-recordings of site-based interviews. The intraclass correlation between site-based and paired site-independent ratings was r = 0.839 for the total PANSS scores (n = 1006) and r = 0.871 for the total BNSS scores (n = 892); <5 % of paired scores deviated outside the acceptable confidence intervals. Ratings "outliers" were identified and remediated. We examined the pattern of paired scoring deviations for the BNSS, total PANSS, PANSS symptom subscales, and the Marder negative symptom factor. Each metric revealed a bidirectional pattern of scoring deviations such that mean site-based ratings were higher than site-independent ratings when symptom severity was high but lower than site-independent ratings when symptom severity was low. The pattern of bidirectional paired scoring deviations observed in this analysis has previously been noted in paired ratings analyses of subjects experiencing an acute exacerbation of psychosis in schizophrenia and major depressive disorder as well. The bidirectional pattern may reflect inherent differences between live ratings and remotely scored recorded ratings. This analysis affirms the utility of video-recordings of site-based ratings for surveillance in trials with subjects with schizophrenia and persistent negative symptoms.

Mild Cognitive Impairment: Clinical Presentation and Short-Term Comparative Outcome of Patients With Potentially Modifiable and Nonmodifiable Risk Factors.

Objective: To estimate the prevalence and study the clinical presentation of mild cognitive impairment (MCI), assess its outcome in terms of cognition and quality of life, identify factors for reversion to baseline, and compare these factors in the modifiable and nonmodifiable risk factor groups.Methods: Individuals aged >50 years with memory/cognitive complaint(s) were screened using the Mini-Cog over 1 year (August 2018-August 2019). Those meeting the DSM-5 criteria for MCI were enrolled, and risk factors (modifiable and nonmodifiable) were noted. Assessments were done using the Hindi version of the Montreal Cognitive Assessment (H-MoCA), the Clinical Dementia Rating (CDR)-Hindi version, and the World Health Organization Quality of Life-Brief Hindi version. Treatment outcome was assessed at 6 months and compared between the risk factor groups. Factors for reversion of MCI were assessed.Results: A total of 124 patients (22.1% of 561 with cognitive complaints) had MCI, and 100 patients (50 patients from the modifiable group and 50 patients from the nonmodifiable group) completed the study. Depression (52%) and hypertension (48%) were common risk factors. End point cognition scores were similar in both groups, with quality of life better in the modifiable group (P = .023). Age was negatively correlated with cognition in total patients and the nonmodifiable group (r =0.283-0.420; P = .002-.004). In total patients, cognition moderately correlated with education and somewhat with quality of life; 31% and 57% reverted to normal on the MoCA and CDR scales, respectively, while 1 progressed to dementia. Reverters had higher baseline H-MoCA scores (odds ratio [OR] = 6.996; P < .001) and were treated with cholinesterase inhibitors + vitamin E (OR = 28.999; P = .007).Conclusion: Short-term outcome for both the modifiable and nonmodifiable risk factor groups was favorable. Higher education positively correlated with cognition, which itself predicted a better quality of life. Reverters of MCI had better baseline cognition and were treated with cholinesterase inhibitors + vitamin E.Prim Care Companion CNS Disord 2024;26(4):24m03708. Author affiliations are listed at the end of this article.

INTERACT: a randomized phase 2 study of the DAAO inhibitor luvadaxistat in adults with schizophrenia.

Deficits in N-methyl-d-aspartate receptor (NMDAR) signaling are implicated in the pathogenesis of schizophrenia. Luvadaxistat (TAK-831/NBI-1065844) is an investigational d-amino acid oxidase (DAAO) inhibitor that increases d-serine levels at NMDAR coagonist sites. INTERACT is a phase 2 randomized, placebo-controlled study that evaluated the efficacy and safety of three doses of luvadaxistat, covering a range of DAAO occupancy and d-serine levels, in patients with schizophrenia with persistent negative symptoms. The study included a 14-day, single-blinded placebo run-in period and a 12-week, double-blinded treatment period. The primary efficacy endpoint was the 12-week change from baseline in Positive and Negative Syndrome Scale-Negative Symptom Factor Score (PANSS NSFS). Secondary efficacy endpoints included the 12-week changes from baseline in Brief Assessment of Cognition in Schizophrenia (BACS) score and Schizophrenia Cognition Rating Scale (SCoRS) score. Safety endpoints included adverse event assessments. The full analysis set included all randomized patients (N = 256 [placebo, n = 87; luvadaxistat 50 mg, n = 58; 125 mg, n = 56; 500 mg, n = 55]); 228 patients completed the study. No significant improvements in PANSS NSFS were observed at any dose versus placebo at week 12. Improvements were observed with luvadaxistat 50 mg versus placebo in cognitive endpoints: BACS composite score (nominal one-sided p = 0.031) and SCoRS interviewer total score (nominal one-sided p = 0.011). Luvadaxistat did not significantly improve negative symptoms of schizophrenia. However, luvadaxistat 50 mg met the prespecified secondary endpoints for cognitive performance (BACS) and function (SCoRS), warranting further investigation in patients with cognitive impairment associated with schizophrenia. Luvadaxistat was well-tolerated in INTERACT, with no new safety signals observed. ClinicalTrials.gov: NCT03382639.

A Comprehensive Analysis of Clinical, Biochemical, and Polysomnographic Characteristics in Patients With Type 2 Diabetes Mellitus With and Without Obstructive Sleep Apnea.

BACKGROUND: Obstructive sleep apnea (OSA) has been a significant contributor to mortality all across the globe. The most attributing factors to pathogenesis are metabolic syndrome, obesity, diabetes, and so on, but the indicators of its early detection are still elusive. OBJECTIVE: The study aimed to compare the clinical, biochemical, and polysomnographic characteristics of type 2 diabetes patients with and without OSA. DESIGN AND METHODS: This cross-sectional study was conducted at the Department of Medicine and Endocrinology Unit of Dayanand Medical College and Hospital, Ludhiana. A total of 584 patients with type 2 diabetes were assessed using the Berlin questionnaire, with 302 fulfilling the criteria for a high risk of OSA. Out of 302 patients who met the criteria for the high-risk category, 110 patients underwent a sleep study. RESULTS:  Three hundred and two patients satisfying the inclusion and exclusion criteria were enrolled in the study. A total of 110 patients underwent a sleep study, of which 68 (61.8%) had evidence of OSA. The waist-to-hip ratio was considerably higher in the OSA patients than in the non-OSA group (1.09 vs 0.930, p = 0.001). HbA1c >7% was found in 58.8% of OSA patients contrary to 38.1% of non-OSA patients. Fasting plasma glucose levels (>126 mg/dl) were identified in a substantially larger proportion of OSA patients than the non-OSA patients (64.7% vs 45.2%, p = 0.04). Similarly, peripheral neuropathy was found more commonly in the OSA patients than in the non-OSA patients (47% vs. 26.1%, p = 0.02). Prevalence of retinopathy, nephropathy, coronary artery disease, stroke, heart failure, and peripheral vascular disease did not differ significantly between the two groups. CONCLUSIONS: OSA frequently occurs among individuals diagnosed with type 2 diabetes mellitus. The prompt identification of OSA within this demographic is imperative to pinpoint those at an elevated risk of succumbing to conditions such as peripheral neuropathy, the exacerbation of glycemic control, and the onset of unmanaged hypertension. Moreover, there exists a positive correlation between the waist-to-hip ratio and the prevalence of OSA in persons with type 2 diabetes mellitus, highlighting the critical role of waist-to-hip ratio assessments in this patient population.

Effects of the selective AMPA modulator NBI-1065845 on the pharmacokinetics of midazolam or ethinyl estradiol-levonorgestrel in healthy adults.

This parallel-arm, phase I study investigated the potential cytochrome P450 (CYP)3A induction effect of NBI-1065845 (TAK-653), an investigational α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiator in phase II development for major depressive disorder. The midazolam treatment arm received the sensitive CYP3A substrate midazolam on Day 1, followed by NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with midazolam, then NBI-1065845 alone on Day 15. The oral contraceptive treatment arm received ethinyl estradiol-levonorgestrel on Day 1, then NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with ethinyl estradiol-levonorgestrel, then NBI-1065845 alone on Days 15-17. Blood samples were collected for pharmacokinetic analyses. The midazolam treatment arm comprised 14 men and 4 women, of whom 16 completed the study. Sixteen of the 17 healthy women completed the oral contraceptive treatment arm. After multiple daily doses of NBI-1065845, the geometric mean ratios (GMRs) (90% confidence interval) for maximum observed concentration were: midazolam, 0.94 (0.79-1.13); ethinyl estradiol, 1.00 (0.87-1.15); and levonorgestrel, 0.99 (0.87-1.13). For area under the plasma concentration-time curve (AUC) from time 0 to infinity, the GMRs were as follows: midazolam, 0.88 (0.78-0.98); and ethinyl estradiol, 1.01 (0.88-1.15). For levonorgestrel, the GMR for AUC from time 0 to the last quantifiable concentration was 0.87 (0.78-0.96). These findings indicate that NBI-1065845 is not a CYP3A inducer and support its administration with CYP3A substrates. NBI-1065845 was generally well tolerated, with no new safety signals observed after coadministration of midazolam, ethinyl estradiol, or levonorgestrel.

CHD7 regulates craniofacial cartilage development via controlling HTR2B expression.

Mutations in the Chromodomain helicase DNA-binding protein 7 - coding gene (CHD7) cause CHARGE syndrome (CS). Although craniofacial and skeletal abnormalities are major features of CS patients, the role of CHD7 in bone and cartilage development remain largely unexplored. Here, using a zebrafish (Danio rerio) CS model, we show that chd7-/- larvae display abnormal craniofacial cartilage development and spinal deformities. The craniofacial and spine defects are accompanied by a marked reduction of bone mineralization. At the molecular level, we show that these phenotypes are associated with significant reduction in the expression levels of osteoblast differentiation markers. Additionally, we detected a marked depletion of collagen 2α1 in the cartilage of craniofacial regions and vertebrae, along with significantly reduced number of chondrocytes. Chondrogenesis defects are at least in part due to downregulation of htr2b, which we found to be also dysregulated in human cells derived from an individual with CHD7 mutation-positive CS. Overall, this study thus unveils an essential role for CHD7 in cartilage and bone development, with potential clinical relevance for the craniofacial defects associated with CS.

Patients with CHARGE syndrome exhibit skeletal defects. CHARGE syndrome is primarily caused by mutations in the chromatin remodeler-coding gene CHD7. To investigate the poorly characterized role of CHD7 in cartilage and bone development, here, we examine the craniofacial and bone anomalies in a zebrafish chd7-/- mutant model. We find that zebrafish mutant larvae exhibit striking dysmorphism of craniofacial structures and spinal deformities. Notably, we find a significant reduction in osteoblast, chondrocyte, and collagen matrix markers. This work provides important insights to improve our understanding of the role of chd7 in skeletal development.

GeneAI 3.0: powerful, novel, generalized hybrid and ensemble deep learning frameworks for miRNA species classification of stationary patterns from nucleotides.

Due to the intricate relationship between the small non-coding ribonucleic acid (miRNA) sequences, the classification of miRNA species, namely Human, Gorilla, Rat, and Mouse is challenging. Previous methods are not robust and accurate. In this study, we present AtheroPoint's GeneAI 3.0, a powerful, novel, and generalized method for extracting features from the fixed patterns of purines and pyrimidines in each miRNA sequence in ensemble paradigms in machine learning (EML) and convolutional neural network (CNN)-based deep learning (EDL) frameworks. GeneAI 3.0 utilized five conventional (Entropy, Dissimilarity, Energy, Homogeneity, and Contrast), and three contemporary (Shannon entropy, Hurst exponent, Fractal dimension) features, to generate a composite feature set from given miRNA sequences which were then passed into our ML and DL classification framework. A set of 11 new classifiers was designed consisting of 5 EML and 6 EDL for binary/multiclass classification. It was benchmarked against 9 solo ML (SML), 6 solo DL (SDL), 12 hybrid DL (HDL) models, resulting in a total of 11 + 27 = 38 models were designed. Four hypotheses were formulated and validated using explainable AI (XAI) as well as reliability/statistical tests. The order of the mean performance using accuracy (ACC)/area-under-the-curve (AUC) of the 24 DL classifiers was: EDL > HDL > SDL. The mean performance of EDL models with CNN layers was superior to that without CNN layers by 0.73%/0.92%. Mean performance of EML models was superior to SML models with improvements of ACC/AUC by 6.24%/6.46%. EDL models performed significantly better than EML models, with a mean increase in ACC/AUC of 7.09%/6.96%. The GeneAI 3.0 tool produced expected XAI feature plots, and the statistical tests showed significant p-values. Ensemble models with composite features are highly effective and generalized models for effectively classifying miRNA sequences.

Pelvic Pseudotumor Associated With a Ceramic Bearing Total Hip.

Pseudotumors have been well documented to occur most frequently in metal-metal bearing total hip arthroplasties and less frequently in metal-polyethylene bearings. There are few cases in the literature of pseudotumors occurring in ceramic-ceramic articulations. We report a case of a large pelvic pseudotumor in a patient with a ceramic-ceramic bearing articulation in a 67-year-old man. In addition to the usual investigations, we did a detailed wear analysis of the ceramic implants and an examination of the soft tissues for particulate debris. The detailed wear analysis did show evidence of stripe wear; however, the volumetric wear was within the expected range. Synchrotron imaging identified strontium and zirconium debris arising from the ceramic surfaces. Although association does not mean causation, no other cause for the large pseudotumor could be identified and presumably represents an idiosyncratic reaction to ceramic debris.

Facile Synthesis of S-doped Carbon Quantum Dots and Their Application in the Detection of Sudan I in Saffron.

This study employed citric acid as a carbon source and thiourea as a sulphur source to conduct a straightforward one-step microwave synthesis of sulphur-doped carbon quantum dots (SCQDs). For the characterization of as-synthesized SCQDs, several methods such as fluorescence spectroscopy, X-Ray photoelectron spectroscopy (XPS), X-Ray diffraction (XRD), and zeta potential analyzer were utilized. XRD and XPS spectroscopy are used to examine the chemical composition and morphological aspects. These QDs have a limited size distribution spanning up to 5.89 nm, with a maximum distribution at 7 nm, according to zeta size analyser examinations. At an excitation wavelength of 340 nm, the highest fluorescence intensity (FL intensity) of SCQDs was attained. With a detection limit of 0.77 M, the synthesized SCQDs were employed as an efficient fluorescent probe for the detection of Sudan I in saffron samples.

NMJ Analyser: a novel method to quantify neuromuscular junction morphology in zebrafish.

MOTIVATION: Neuromuscular junction (NMJ) structural integrity is crucial for transducing motor neuron signals that initiate skeletal muscle contraction. Zebrafish has emerged as a simple and efficient model to study NMJ structural morphology and function in the context of developmental neurobiology and neuromuscular diseases. However, methods to quantify NMJ morphology from voluminous data of NMJ confocal images accurately, rapidly, and reproducibly are lacking. RESULTS: We developed an ImageJ macro called "NMJ Analyser" to automatically and unbiasedly analyse NMJ morphology in zebrafish. From the Z-stack of a zebrafish hemisomite, both presynaptic and postsynaptic fluorescently labeled termini at NMJs are extracted from background signal, with larger clusters of termini being segmented into individual termini using an unbiased algorithm. The program then determines whether each presynaptic terminus is co-localized with a postsynaptic terminus and vice versa, or whether it is orphaned, and tabulates the number of orphan and co-localized pre- and postsynaptic termini. The usefulness of this ImageJ macro plugin will be helpful to quantify NMJ parameters in zebrafish, particularly during development and in disease models of neuromuscular diseases. It can enable high-throughput NMJ phenotypic screens in the drug discovery process for neuromuscular diseases. It could also be further applied to the investigation of NMJ of other developmental systems. AVAILABILITY AND IMPLEMENTATION: NMJ Analyser is available for download at https://github.com/PattenLab/NMJ-Analyser.git.

Intact Bulla Versus Trans-Axillary: Which is a Better Approach to Frontal Sinus?

Background: Frontal sinus is one of the most difficult sinuses to approach endoscopically because of its anatomical location. Challenges and difference in opinions still exist in terms of its surgical management. Endoscopic approach to frontal sinus commonly involves either trans-axillary or intact bulla technique. Trans-axillary technique gives a direct access to the frontal sinus even with a 0° endoscope whereas Intact bulla technique warrants the use of 70° scope. Despite both the techniques now existing for quite some time; literature is still controversial regarding the superiority of one technique over the other. Methods and Materials: A randomised prospective study of 40 patients of frontal sinusitis. Patients were randomly allocated into two groups. In approaching frontal sinus, groupA patients underwent trans-axillary technique and group B patients underwent intact bulla technique. Both the groups were statistically compared in terms of time taken for surgery, post operative results and improvement in symptom score. Results: The pre-operative endoscopic Lund -Kennedy score in group A was 7.1 ± 1.57 while in group B was 6.95 ± 1.1. The mean post -operative endoscopic Lund Kennedy score in group A was 1.25 ± 0.93. and in group B was 1.05 ± 0.89. The mean pre& SNOT-22 score in group A was 79.85 ± 19.1 and in group B was 80.55 ± 16.94. The mean postoperative SNOT-22 Score in Group A was 4.450 ± 2.136 and group B was 2.579 ± 1. 714.The average time taken in group A to reach frontal sinus was 21.1 ± 5.44 min while in group B it was15.9 ± 3.6 min. At 12 weeks follow up recurrence was seen in 4/20 cases in group A and 3/20 Cases in group B. Ostial Stenosis was seen in 3/20 cases in group A and 2/20 cases in group B. Nasal adhesions were seen in 7/20 cases in group A and 1/20 cases in group B. Middle turbinate lateralization was seen in 8/20 cases in group A and 1/19 cases in group B. Lamina Papyracea injury was seen in 1 case in group B but in 3 cases of group A. Conclusion: Both the techniques were highly efficacious in improving post-operative endoscopic as well as symptom scores. However, some post operative complications like middle turbinate lateralization were more with trans-axillary technique as compared to intact bulla technique.

DermAI 1.0: A Robust, Generalized, and Novel Attention-Enabled Ensemble-Based Transfer Learning Paradigm for Multiclass Classification of Skin Lesion Images.

Skin lesion classification plays a crucial role in dermatology, aiding in the early detection, diagnosis, and management of life-threatening malignant lesions. However, standalone transfer learning (TL) models failed to deliver optimal performance. In this study, we present an attention-enabled ensemble-based deep learning technique, a powerful, novel, and generalized method for extracting features for the classification of skin lesions. This technique holds significant promise in enhancing diagnostic accuracy by using seven pre-trained TL models for classification. Six ensemble-based DL (EBDL) models were created using stacking, softmax voting, and weighted average techniques. Furthermore, we investigated the attention mechanism as an effective paradigm and created seven attention-enabled transfer learning (aeTL) models before branching out to construct three attention-enabled ensemble-based DL (aeEBDL) models to create a reliable, adaptive, and generalized paradigm. The mean accuracy of the TL models is 95.30%, and the use of an ensemble-based paradigm increased it by 4.22%, to 99.52%. The aeTL models' performance was superior to the TL models in accuracy by 3.01%, and aeEBDL models outperformed aeTL models by 1.29%. Statistical tests show significant p-value and Kappa coefficient along with a 99.6% reliability index for the aeEBDL models. The approach is highly effective and generalized for the classification of skin lesions.

3D printing for spine pathologies: a state-of-the-art review.

Three-Dimensional Printing has advanced throughout the years in the field of biomedical science with applications, especially in spine surgeries. 3D printing has the ability of fabricating highly complex structures with ease and high dimensional accuracy. The complexity of the spine's architecture and the inherent dangers of spinal surgery bring the evaluation of 3D printed models into consideration. This article summarizes the benefits of 3D printing based models for application in spine pathology. 3D printing technique is extensively used for fabrication of anatomical models, surgical guides and patient specific implants (PSI). The 3D printing based anatomical models assist in preoperative planning and training of students. Furthermore, 3D printed models can be used for improved communication and understanding of patients about the spinal disorders. The use of 3D printed surgical guides help in the stabilization of the spine during surgery, improving post procedural outcomes. Improved surgical results can be achieved by using PSIs that are tailored for patient specific needs. Finally, this review discusses the limitations and potential future scope of 3D printing in spine pathologies. 3D printing is still in its infancy, and further research would provide better understanding of the technology's true potential in spinal procedures.

Effect of Microdissection of Inferior Thyroid Artery on Post-operative Hypocalcemia in Total Thyroidectomy.

Hypocalcemia is one of the most common complication after bilateral thyroid surgery. Reported rates range from 5 to 35% and 0.5 to 4.4% for transient and permanent hypocalcemia respectively. Various methods have been devised to reduce the post-operative hypocalcemia and range from modification of surgical techniques to use of loops and avoidance of inadverant neck dissections. We conducted a randomised control trial of 50 patients divided into two groups, to evaluate the effect of microdissection and ligation of distal branches of inferior thyroid artery (group B) on incidence of temporary and permanent hypocalcaemia in patients of total thyroidectomy versus its ligation distally close to the thyroid capsule(group A). Postoperative mean total serum calcium levels were lower in group A as compared to group B (9.13 mg/dl vs. 9.33 mg/dl at 24 h; 8.77 vs. 9.10 at 3rd day and 8.58 vs. 8.96 mg/dl on 10 th day) with p > 0.05. The value of ionized serum calcium as recorded on 3rd day was 4.39 mg/dl for group A and 4.72 mg/dl for group B with p value ≤ 0.001 (Table 2). 19 patients in group A required calcium supplementation for 6 months with incidence of transient hypocalcemia at 76% while 11 patients in group B had calcium supplementation for 6 months with incidence of 40% and difference was significant statistically. Microdissection technique is better for preventing the temporary hypocalcemia and hence decreasing the hospital visits of the patient when compared to the ligation of inferior thyroid artery distally close to the thyroid gland. The incidence of permanent hypocalcemia doesn't varies significantly between both techniques.

Smart Farming Revolution: Portable and Real-Time Soil Nitrogen and Phosphorus Monitoring for Sustainable Agriculture.

Precision agriculture is crucial for ensuring food security in a growing global population. Nutrients, their presence, concentration, and effectiveness, are key components in data-driven agriculture. Assessing macro and micro-nutrients, as well as factors such as water and pH, helps determine soil fertility, which is vital for supporting healthy plant growth and high crop yields. Insufficient soil nutrient assessment during continuous cropping can threaten long-term agricultural viability. Soil nutrients need to be measured and replenished after each harvest for optimal yield. However, existing soil testing procedures are expensive and time-consuming. The proposed research aims to assess soil nutrient levels, specifically nitrogen and phosphorus concentrations, to provide critical information and guidance on restoring optimal soil fertility. In this research, a novel chip-level colorimeter is fabricated to detect the N and P elements of soil onto a handheld colorimeter or spectrophotometer. Chemical reaction with soil solution generates color in the presence of nutrients, which are then quantitatively measured using sensors. The test samples are collected from various farmlands, and the results are validated with laboratory analysis of samples using spectrophotometers used in laboratories. ANOVA test has been performed in which F value > 1 in our study indicates statistically significant differences between the group means. The alternate hypothesis, which proposes the presence of significant differences between the groups, is supported by the data. The device created in this paper has crucial potential in terms of environmental and biological applications.

Pharmacokinetics of Nasal Esketamine in Patients with Allergic Rhinitis with and Without Nasal Decongestant Pretreatment and in Healthy Subjects with and Without Nasal Corticosteroid Pretreatment.

BACKGROUND AND OBJECTIVES: Nasal esketamine is indicated for the treatment of adults with treatment-resistant depression and depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. Primary objectives of this study were to evaluate the effect of nasal decongestant pretreatment in patients with allergic rhinitis and the impact of daily nasal corticosteroid administration by healthy subjects on nasal esketamine pharmacokinetics. METHODS: Patients with allergic rhinitis self-administered 56 mg of nasal esketamine after pretreatment with nasal oxymetazoline (0.05%) at 1 h before esketamine and without oxymetazoline pretreatment. They were exposed to grass pollen in an allergen challenge chamber to induce allergic rhinitis symptoms at approximately 2 h before each esketamine administration until 1 h after. Healthy subjects self-administered esketamine (56 mg) before and after administration for 16 consecutive days of mometasone (200 µg), with the second esketamine dose administered 1 h after the last mometasone dose. The plasma pharmacokinetics of esketamine and noresketamine were assessed after each esketamine administration. The tolerability of esketamine, including effects on dissociative and potential psychotomimetic symptoms and level of sedation and suicidal ideation and behavior, was evaluated. RESULTS: The rate of esketamine absorption was slightly greater in patients exhibiting symptoms of allergic rhinitis (decrease in median tmax from 32 min to 22 min). Increases in esketamine Cmax and AUC were also small (mean, ≤ 21%). The pharmacokinetics of esketamine was not affected by oxymetazoline or mometasone pretreatment. Esketamine was well tolerated when it was administered with or without pretreatment of oxymetazoline or mometasone. CONCLUSIONS: Patients exhibiting symptoms of rhinitis may receive nasal esketamine spray without dose adjustment. In addition, esketamine may be administered 1 h after using a nasal decongestant or corticosteroid. TRIAL REGISTRATION: The study was registered in the Clinical Trials (NCT02154334) and EudraCT (2014-000534-38) registries.

Attention-Enabled Ensemble Deep Learning Models and Their Validation for Depression Detection: A Domain Adoption Paradigm.

Depression is increasingly prevalent, leading to higher suicide risk. Depression detection and sentimental analysis of text inputs in cross-domain frameworks are challenging. Solo deep learning (SDL) and ensemble deep learning (EDL) models are not robust enough. Recently, attention mechanisms have been introduced in SDL. We hypothesize that attention-enabled EDL (aeEDL) architectures are superior compared to attention-not-enabled SDL (aneSDL) or aeSDL models. We designed EDL-based architectures with attention blocks to build eleven kinds of SDL model and five kinds of EDL model on four domain-specific datasets. We scientifically validated our models by comparing "seen" and "unseen" paradigms (SUP). We benchmarked our results against the SemEval (2016) sentimental dataset and established reliability tests. The mean increase in accuracy for EDL over their corresponding SDL components was 4.49%. Regarding the effect of attention block, the increase in the mean accuracy (AUC) of aeSDL over aneSDL was 2.58% (1.73%), and the increase in the mean accuracy (AUC) of aeEDL over aneEDL was 2.76% (2.80%). When comparing EDL vs. SDL for non-attention and attention, the mean aneEDL was greater than aneSDL by 4.82% (3.71%), and the mean aeEDL was greater than aeSDL by 5.06% (4.81%). For the benchmarking dataset (SemEval), the best-performing aeEDL model (ALBERT+BERT-BiLSTM) was superior to the best aeSDL (BERT-BiLSTM) model by 3.86%. Our scientific validation and robust design showed a difference of only 2.7% in SUP, thereby meeting the regulatory constraints. We validated all our hypotheses and further demonstrated that aeEDL is a very effective and generalized method for detecting symptoms of depression in cross-domain settings.

Assessment of health-related quality of life and health status in patients with treatment-resistant depression treated with esketamine nasal spray plus an oral antidepressant.

BACKGROUND: Patients with treatment-resistant depression (TRD) report significant deficits in physical and mental health, as well as severely impaired health-related quality of life (HRQoL) and functioning. Esketamine effectively enhances the daily functioning in these patients while also improving their depressive symptoms. This study assessed HRQoL and health status of patients with TRD, who were treated with esketamine nasal spray and an oral antidepressant (ESK + AD) vs. placebo nasal spray and an AD (AD + PBO). METHODS: Data from TRANSFORM-2, a phase 3, randomized, double-blind, short-term flexibly dosed study, were analyzed. Patients (aged 18-64 years) with TRD were included. The outcome assessments included the European Quality of Life Group, Five Dimension, Five Level (EQ-5D-5L), EQ-Visual Analogue Scale (EQ-VAS), and Sheehan Disability Scale (SDS). The health status index (HSI) was calculated using EQ-5D-5L scores. RESULTS: The full analysis set included 223 patients (ESK + AD: 114; AD + PBO: 109; mean [SD] age: 45.7 [11.89]). At Day 28, a lower percentage of patients reported impairment in the ESK + AD vs. AD + PBO group in all five EQ-5D-5L dimensions: mobility (10.6% vs. 25.0%), self-care (13.5% vs. 32.0%), usual activities (51.9% vs. 72.0%), pain/discomfort (35.6% vs. 54.0%), and anxiety/depression (69.2% vs. 78.0%). The mean (SD) change from baseline in HSI at Day 28 was 0.310 (0.219) for ESK + AD and 0.235 (0.252) for AD + PBO, with a higher score reflecting better levels of health. The mean (SD) change from baseline in EQ-VAS score at Day 28 was greater in ESK + AD (31.1 [25.67]) vs. AD + PBO (22.1 [26.43]). The mean (SD) change in the SDS total score from baseline to Day 28 also favored ESK + AD (-13.6 [8.31]) vs. AD + PBO (-9.4 [8.43]). CONCLUSIONS: Greater improvements in HRQoL and health status were observed among patients with TRD treated with ESK + AD vs. AD + PBO. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02418585.