Randomized clinical trial of low dose suramin intravenous infusions for treatment of autism spectrum disorder.

BACKGROUND: There is a critical need for effective treatment of the core symptoms of autism spectrum disorder (ASD). The purinergic antagonist suramin may improve core symptoms through restoration of normal mitochondrial function and reduction of neuro-inflammation via its known antagonism of P2X and P2Y receptors. Nonclinical studies in fragile X knockout mice and the maternal immune activation model support these hypotheses. METHODS: We conducted a 14 week, randomized, double-blind, placebo-controlled proof -of-concept study (N = 52) to test the efficacy and safety of suramin intravenous infusions in boys aged 4-15 years with moderate to severe ASD. The study had 3 treatment arms: 10 mg/kg suramin, 20 mg/kg suramin, and placebo given at baseline, week 4, and week 8. The Aberrant Behavior Checklist of Core Symptoms (ABC-Core) (subscales 2, 3, and 5) was the primary endpoint and the Clinical Global Impressions-Improvement (CGI-I) was a secondary endpoint. RESULTS: Forty-four subjects completed the study. The 10 mg/kg suramin group showed a greater, but statistically non-significant, numeric improvement (- 12.5 ± 3.18 [mean ± SE]) vs. placebo (- 8.9 ± 2.86) in ABC-Core at Week 14. The 20 mg/kg suramin group did not show improvement over placebo. In exploratory analyses, the 10 mg/kg arm showed greater ABC Core differences from placebo in younger subjects and among those with less severe symptoms. In CGI-I, the 10 mg/kg arm showed a statistically significant improvement from baseline (2.8 ± 0.30 [mean ± SE]) compared to placebo (1.7 ± 0.27) (p = 0.016). The 20 mg/kg arm had a 2.0 ± 0.28 improvement in CGI-I, which was not statistically significant compared to placebo (p = 0.65). CONCLUSION: Suramin was generally safe and well tolerated over 14 weeks; most adverse events were mild to moderate in severity. Trial Registration Registered with the South African Health Authority, registration number DOH-27-0419-6116. CLINICALTRIALS: Gov registration ID is NCT06058962, last update posted 2023-09-28.

Safety and Efficacy of CT-Guided Percutaneous Biopsy of Suspicious Subcentimeter Pelvic and Retroperitoneal Lymph Nodes Detected by 11C-Choline PET in Patients With Prostate Cancer.

BACKGROUND. In patients with prostate cancer, PET using targeted radiotracers can identify increased activity in small morphologically normal lymph nodes, facilitating earlier detection of metastatic disease. OBJECTIVE. The purpose of this article was to assess the efficacy and safety of CT-guided biopsy of suspicious pelvic and retroperitoneal lymph nodes measuring smaller than 1 cm detected by 11C-choline PET in patients with prostate cancer, with comparison with nodes measuring 1 cm or larger. METHODS. This retrospective study included patients with prostate cancer who underwent CT-guided percutaneous biopsy of suspicious pelvic or retroperitoneal lymph nodes detected by 11C-choline PET/CT or PET/MRI (performed because of a rising or elevated PSA level or known recurrent or metastatic disease) between June 1, 2012, and March 20, 2020. Patient, lymph node, and procedural characteristics, as well as biopsy outcomes and complications, were recorded. Biopsies of lymph nodes measuring smaller than 1 cm and of lymph nodes measuring 1 cm and larger were compared. RESULTS. A total of 269 patients (mean age, 68.7 ± 6.8 [SD] years) were included. A total of 156 patients underwent biopsy of lymph nodes measuring smaller than 1 cm (range, 3-9 mm); 113 patients underwent biopsy of lymph nodes measuring 1 cm or larger (range, 10-35 mm). Lymph nodes smaller than 1 cm and lymph nodes 1 cm and larger showed no significant difference in diagnostic yield (89.7% vs 92.9%; p = .40). Diagnostic yield was not significantly different between nodes smaller than 1 cm and nodes 1 cm and larger for any individual anatomic location within the pelvis or retroperitoneum (all p > .05). Malignant yield was lower for nodes smaller than 1 cm than for nodes 1 cm and larger (44.9% vs 63.7%; p = .003). The single biopsied 3-mm node had a nondiagnostic specimen. Diagnostic yield and malignant yield were 100.0% and 40.0%, respectively, for 4-mm nodes, and 95.5% and 45.5%, respectively, for 5-mm nodes. Patients with nodes smaller than 1 cm and nodes 1 cm and larger showed no significant difference in minor (12.8% vs 7.1%; p = .16) or major (0.6% vs 2.7%; p = .31) complication rate. CONCLUSION. The findings support the safety and efficacy of CT-guided biopsy of suspicious subcentimeter pelvic and retroperitoneal lymph nodes detected on 11C-choline PET in patients with prostate cancer. CLINICAL IMPACT. Earlier diagnosis of metastatic lymphadenopathy will impact prognostic assessment and management decisions in patients with recurrent prostate cancer.

Postoperative surveillance of pancreatic ductal adenocarcinoma (PDAC) recurrence: practice pattern on standardized imaging and reporting from the society of abdominal radiology disease focus panel on PDAC.

PURPOSE: Surgical resection is the only potential curative treatment for patients with pancreatic ductal adenocarcinoma (PDAC), but unfortunately most patients recur within 5 years of surgery. This article aims to assess the practice patterns across major academic institutions and develop consensus recommendations for postoperative imaging and interpretation in patients with PDAC. METHODS: The consensus recommendations for postoperative imaging surveillance following PDAC resection were developed using the Delphi method. Members of the Society of Abdominal Radiology (SAR) PDAC Disease Focused Panel (DFP) underwent three rounds of surveys followed by live webinar group discussions to develop consensus recommendations. RESULTS: Significant variations currently exist in the postoperative surveillance of PDAC, even among academic institutions. Differentiating common postoperative inflammatory and fibrotic changes from tumor recurrence remains a diagnostic challenge, and there is no reliable size threshold or growth rate of imaging findings that can provide differentiation. A new liver lesion or peritoneal nodule should be considered suspicious for tumor recurrence, and the imaging features should be interpreted in the appropriate clinical context (e.g., CA 19-9, clinical presentation, pathologic staging). CONCLUSION: Postoperative imaging following PDAC resection is challenging to interpret due to the presence of confounding postoperative inflammatory changes. A standardized reporting template for locoregional findings and report impression may improve communication of relaying risk of recurrence with referring providers, which merits validation in future studies.

Comparison of Long-Term Efficacy and Safety of Esketamine Nasal Spray Plus Oral Antidepressant in Younger Versus Older Patients With Treatment-Resistant Depression: Post-Hoc Analysis of SUSTAIN-2, a Long-Term Open-Label Phase 3 Safety and Efficacy Study.

BACKGROUND: Older, compared with younger, patients with treatment-resistant depression (TRD) typically have lower response and remission rates with poorer tolerability to antidepressant treatment. This post-hoc analysis compared outcomes following treatment with esketamine nasal spray (ESK) between younger (18-64 years) and older (≥65 years) patients with TRD. METHODS: SUSTAIN-2, an up to 1-year open-label safety and efficacy study of ESK plus an oral antidepressant, included patients with TRD either directly enrolled (≥18-year) or transferred from a phase 3 double-blind study, TRANSFORM-3 (≥65-year). Patients were treated in two phases: 4-week induction and 48-week optimization/maintenance. RESULTS: Younger (n = 624) and older (n = 178) patients had similar baseline characteristics except for hypertension history (21.5% versus 48.3%, respectively). Patients (younger versus older) had similar mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total scores and mean (SD) reductions in MADRS total scores for induction (-18.0 [7.19] versus -18.1 [9.37]; p = 0.492 [t = 0.69, df = 701]) and optimization/maintenance (week 12) (-19.9 [7.03] versus -22.2 [9.50]; p = 0.265 [t = -1.12, df = 3470]) phases. Treatment-emergent adverse events (TEAEs) reported in younger versus older patients, respectively, were: induction, 86.1% versus 74.8%; optimization/maintenance, 86.8% versus 81.0%; serious TEAEs: induction, 2.2% versus 1.9%; optimization/maintenance, 6.7% versus 4.8%; TEAEs of increased blood pressure: induction, 6.9% versus 6.5%; optimization/maintenance, 7.1% versus 9.5%; and falls: induction, 0.3% versus 0.6%; optimization/maintenance, 0.2% versus 0.8%. Cognitive tests did not show clinically meaningful differences between the age groups. CONCLUSIONS: Although limited by the open-label design of SUSTAIN-2, this post-hoc analysis showed generally comparable improvement in depression between ESK-treated younger and older adult patients with TRD, with consistent safety outcomes.

Phage-encoded ten-eleven translocation dioxygenase (TET) is active in C5-cytosine hypermodification in DNA.

TET/JBP (ten-eleven translocation/base J binding protein) enzymes are iron(II)- and 2-oxo-glutarate-dependent dioxygenases that are found in all kingdoms of life and oxidize 5-methylpyrimidines on the polynucleotide level. Despite their prevalence, few examples have been biochemically characterized. Among those studied are the metazoan TET enzymes that oxidize 5-methylcytosine in DNA to hydroxy, formyl, and carboxy forms and the euglenozoa JBP dioxygenases that oxidize thymine in the first step of base J biosynthesis. Both enzymes have roles in epigenetic regulation. It has been hypothesized that all TET/JBPs have their ancestral origins in bacteriophages, but only eukaryotic orthologs have been described. Here we demonstrate the 5mC-dioxygenase activity of several phage TETs encoded within viral metagenomes. The clustering of these TETs in a phylogenetic tree correlates with the sequence specificity of their genomically cooccurring cytosine C5-methyltransferases, which install the methyl groups upon which TETs operate. The phage TETs favor Gp5mC dinucleotides over the 5mCpG sites targeted by the eukaryotic TETs and are found within gene clusters specifying complex cytosine modifications that may be important for DNA packaging and evasion of host restriction.

Society of Abdominal Radiology Disease Focused Panel Survey on Clinical Utilization of Incidental Pancreatic Cyst Management Recommendations and Template Reporting.

OBJECTIVE: To assess current practice patterns with respect to protocols used for incidental pancreatic cyst follow-up, management guidelines, and template reporting. METHODS: The Society of Abdominal Radiology Disease Focused Panel on intraductal pancreatic neoplasms distributed an anonymous 14-question survey to its members in June 2018 that focused on current utilization of incidental pancreatic cyst guidelines, protocols, and template reporting. RESULTS: Among the 1,390 email invitations, 323 responded, and 94.7% (306 of 323) completed all questions. Respondents were mainly radiologists (93.8%, 303 of 323) from academic institutions (74.7%, 227 of 304) in North America (93.7%, 286 of 305). Of respondents, 42.5% (136 of 320) preferred 2017 ACR recommendations, 17.8% (57 of 320) homegrown systems, 15.0% (48 of 320) Fukuoka guidelines, and 7.8% (25 of 320) American Gastroenterological Association guidelines. The majority (68.7%, 222 of 323) agreed or strongly agreed that developing a single international consensus recommendation for management was important, and most radiologists preferred to include them in reports (231 of 322, 71.7%); yet only half included recommendations in >75% of reports (161 of 321). MR cholangiopancreatography was the modality of choice for follow-up of <2.5 cm cysts. Intravenous contrast was routinely used by 69.7% (212 of 304). Standardized reporting templates were rarely used in practice (12.8% 39 of 306). CONCLUSIONS: Nearly 7 of 10 radiologists desire a unified international consensus recommendation for management of incidental cystic pancreatic lesions; ACR 2017 recommendations are most commonly used, followed by homegrown systems and Fukuoka guidelines. The majority of radiologists routinely use MR cholangiopancreatography with intravenous contrast for follow-up of incidental cystic lesions, but template reporting is rarely used.

Esketamine Nasal Spray for Rapid Reduction of Depressive Symptoms in Patients With Major Depressive Disorder Who Have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II).

BACKGROUND: Patients with major depressive disorder (MDD) having active suicidal ideation with intent require immediate treatment. METHODS: This double-blind study (ASPIRE II) randomized adults (aged 18-64 years) with MDD having active suicidal ideation with intent to esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks, given with comprehensive standard of care (hospitalization ≥5 days and newly initiated or optimized oral antidepressant[s]). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale total score (primary efficacy endpoint) was analyzed using ANCOVA. Clinical Global Impression-Severity of Suicidality-revised (key secondary endpoint) was analyzed using ANCOVA on ranks of change. RESULTS: Of 230 patients who were randomized (115 per arm), 227 received study drug and were included in efficacy/safety analyses; 184 (80.0%) completed double-blind treatment. Greater improvement in Montgomery-Asberg Depression Rating Scale total score was observed with esketamine (mean [SD]: -15.7 [11.56]) vs placebo (-12.4 [10.43]), each with standard of care, at 24 hours (least-squares mean difference [SE]: -3.9 [1.39], 95% CI: -6.60, -1.11; 2-sided P = .006). This was also noted at the earlier (4-hour) timepoint (least-squares mean difference -4.2, 95% CI: -6.38, -1.94). Patients in both treatment groups experienced rapid reduction in Clinical Global Impression-Severity of Suicidality-revised score; the between-group difference was not statistically significant. The most common adverse events among esketamine-treated patients were dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia. CONCLUSION: This study confirmed rapid and robust reduction of depressive symptoms with esketamine nasal spray in severely ill patients with MDD who have active suicidal ideation with intent. Trial Registration: Clinical Trials.gov identifier: NCT03097133.

Application of artificial intelligence using a novel EUS-based convolutional neural network model to identify and distinguish benign and malignant hepatic masses.

BACKGROUND AND AIMS: Detection and characterization of focal liver lesions (FLLs) is key for optimizing treatment for patients who may have a primary hepatic cancer or metastatic disease to the liver. This is the first study to develop an EUS-based convolutional neural network (CNN) model for the purpose of identifying and classifying FLLs. METHODS: A prospective EUS database comprising cases of FLLs visualized and sampled via EUS was reviewed. Relevant still images and videos of liver parenchyma and FLLs were extracted. Patient data were then randomly distributed for the purpose of CNN model training and testing. Once a final model was created, occlusion heatmap analysis was performed to assess the ability of the EUS-CNN model to autonomously identify FLLs. The performance of the EUS-CNN for differentiating benign and malignant FLLs was also analyzed. RESULTS: A total of 210,685 unique EUS images from 256 patients were used to train, validate, and test the CNN model. Occlusion heatmap analyses demonstrated that the EUS-CNN model was successful in autonomously locating FLLs in 92.0% of EUS video assets. When evaluating any random still image extracted from videos or physician-captured images, the CNN model was 90% sensitive and 71% specific (area under the receiver operating characteristic [AUROC], 0.861) for classifying malignant FLLs. When evaluating full-length video assets, the EUS-CNN model was 100% sensitive and 80% specific (AUROC, 0.904) for classifying malignant FLLs. CONCLUSIONS: This study demonstrated the capability of an EUS-CNN model to autonomously identify FLLs and to accurately classify them as either malignant or benign lesions.

Benefit-Risk Assessment of Esketamine Nasal Spray vs. Placebo in Treatment-Resistant Depression.

This post hoc analysis assessed the benefit-risk profile of esketamine nasal spray + oral antidepressant (AD) induction and maintenance treatment in patients with treatment-resistant depression (TRD). The Benefit-Risk Action Team framework was utilized to assess the benefit-risk profile using data from three induction studies and one maintenance study. Benefits were proportion of remitters or responders in induction studies and proportion of stable remitters or stable responders who remained relapse-free in the maintenance study. Risks were death, suicidal ideation, most common adverse events (AEs), and potential long-term risks. Per 100 patients on esketamine + AD vs. AD + placebo in induction therapy, 5-21 additional patients would remit and 14-17 additional patients would respond. In maintenance therapy, 19-32 fewer relapses would occur with esketamine. In both cases, there was little difference in serious or severe common AEs (primarily dissociation, vertigo, and dizziness). These findings support a positive benefit-risk balance for esketamine + AD as induction and maintenance treatment in patients with TRD.

Utilisation of artificial intelligence for the development of an EUS-convolutional neural network model trained to enhance the diagnosis of autoimmune pancreatitis.

OBJECTIVE: The diagnosis of autoimmune pancreatitis (AIP) is challenging. Sonographic and cross-sectional imaging findings of AIP closely mimic pancreatic ductal adenocarcinoma (PDAC) and techniques for tissue sampling of AIP are suboptimal. These limitations often result in delayed or failed diagnosis, which negatively impact patient management and outcomes. This study aimed to create an endoscopic ultrasound (EUS)-based convolutional neural network (CNN) model trained to differentiate AIP from PDAC, chronic pancreatitis (CP) and normal pancreas (NP), with sufficient performance to analyse EUS video in real time. DESIGN: A database of still image and video data obtained from EUS examinations of cases of AIP, PDAC, CP and NP was used to develop a CNN. Occlusion heatmap analysis was used to identify sonographic features the CNN valued when differentiating AIP from PDAC. RESULTS: From 583 patients (146 AIP, 292 PDAC, 72 CP and 73 NP), a total of 1 174 461 unique EUS images were extracted. For video data, the CNN processed 955 EUS frames per second and was: 99% sensitive, 98% specific for distinguishing AIP from NP; 94% sensitive, 71% specific for distinguishing AIP from CP; 90% sensitive, 93% specific for distinguishing AIP from PDAC; and 90% sensitive, 85% specific for distinguishing AIP from all studied conditions (ie, PDAC, CP and NP). CONCLUSION: The developed EUS-CNN model accurately differentiated AIP from PDAC and benign pancreatic conditions, thereby offering the capability of earlier and more accurate diagnosis. Use of this model offers the potential for more timely and appropriate patient care and improved outcome.

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas: recommendations for Standardized Imaging and Reporting from the Society of Abdominal Radiology IPMN disease focused panel.

There have been many publications detailing imaging features of malignant transformation of intraductal papillary mucinous neoplasms (IPMN), management and recommendations for imaging follow-up of diagnosed or presumed IPMN. However, there is no consensus on several practical aspects of imaging IPMN that could serve as a clinical guide for radiologists and enable future data mining for research. These aspects include how to measure IPMN, define reporting terminology, standardize reporting and unify guidelines for surveillance. The Society of Abdominal Radiology (SAR) created multiple Disease-Focused Panels (DFP) comprised multidisciplinary panel members who focus on a particular disease, with the goal to develop ways for radiologists to improve patient care, education, and research. DFP members met to identify the current controversies and limitations of imaging pancreatic IPMN. This paper aims to provide a practical review of the key imaging characteristics of IPMN for trainees and practicing radiologists, to guide uniformity of performance and interpretation of surveillance imaging studies, and to improve communication with clinicians by providing a lexicon and reporting template based on the experience of the SAR-DFP panel members.

Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I).

OBJECTIVE: To compare esketamine to placebo, each in addition to standard-of-care treatment, for rapidly reducing major depressive disorder symptoms, including suicidal ideation. METHODS: This phase 3, double-blind, multicenter study (ASPIRE I), conducted between June 2017 and December 2018, enrolled 226 adults having major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) criteria, active suicidal ideation with intent, and need for psychiatric hospitalization. Patients were randomized 1:1 to esketamine 84 mg or placebo nasal spray twice-weekly for 4 weeks, each with comprehensive standard-of-care treatment (initial psychiatric hospitalization and newly initiated or optimized oral antidepressant[s] therapy). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale (MADRS) total score (primary endpoint) was analyzed using analysis of covariance (ANCOVA), and change in Clinical Global Impression of Severity of Suicidality Revised version (CGI-SS-r; key secondary endpoint) score was analyzed using ANCOVA on ranks with treatment difference estimated using the Hodges-Lehmann estimate. RESULTS: Greater improvement in MADRS total score was observed with esketamine + standard-of-care versus placebo + standard-of-care at 24 hours (least-squares mean difference [SE]: -3.8 [1.39]; 95% CI, -6.56 to -1.09; 2-sided P = .006), as well as at earlier (4 hours) and later time points during 4-week double-blind treatment. The difference between groups in the severity of suicidality was not statistically significant (median of treatment difference [95% CI]: 0.0 [-1.00 to 0.00]; 2-sided P = .107). The most common adverse events among esketamine-treated patients were dizziness, dissociation, headache, nausea, and somnolence. CONCLUSIONS: These findings demonstrate rapid and robust efficacy of esketamine nasal spray in reducing depressive symptoms in severely ill patients with major depressive disorder who have active suicidal ideation with intent. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03039192.

Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2).

OBJECTIVE: To evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant (OAD) in patients with treatment-resistant depression (TRD). METHODS: This phase 3, open-label, multicenter, long-term (up to 1 year) study was conducted between October 2015 and October 2017. Patients (≥ 18 years) with TRD (DSM-5 diagnosis of major depressive disorder and nonresponse to ≥ 2 OAD treatments) were enrolled directly or transferred from a short-term study (patients aged ≥ 65 years). Esketamine nasal spray (28-mg, 56-mg, or 84-mg) plus new OAD was administered twice a week in a 4-week induction (IND) phase and weekly or every-other-week for patients who were responders and entered a 48-week optimization/maintenance (OP/MAINT) phase. RESULTS: Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry; 580 (74.5%) of 779 patients who entered the IND phase completed the phase, and 150 (24.9%) of 603 who entered the OP/MAINT phase completed the phase. Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Seventy-six patients (9.5%) discontinued esketamine due to TEAEs. Fifty-five patients (6.9%) experienced serious TEAEs. Most TEAEs occurred on dosing days, were mild or moderate in severity, and resolved on the same day. Two deaths were reported; neither was considered related to esketamine. Cognitive performance generally either improved or remained stable postbaseline. There was no case of interstitial cystitis or respiratory depression. Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose. Montgomery-Åsberg Depression Rating Scale total score decreased during the IND phase, and this reduction persisted during the OP/MAINT phase (mean [SD] change from baseline of respective phase to endpoint: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]). CONCLUSIONS: Long-term esketamine nasal spray plus new OAD therapy had a manageable safety profile, and improvements in depression appeared to be sustained in patients with TRD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02497287.

Cognitive functioning in adolescents with schizophrenia treated with paliperidone extended-release: 6-Month exploratory analysis from an open-label, single-arm safety study.

OBJECTIVE: To assess cognitive functioning in adolescents (12-17 years old) with schizophrenia during open-label treatment with paliperidone extended-release (pali ER). METHODS: In this exploratory analysis, adolescents treated with pali ER (oral, flexibly dosed, 1.5-12 mg/day) underwent cognitive assessments at baseline and month 6 using a battery of cognitive tests validated in adolescents. Correlation analysis was used to explore the relationship between cognitive assessments and clinical symptoms (Positive and Negative Syndrome Scales [PANSS] and factors) and functionality (Children Global Assessment Scale [CGAS]) at baseline and at 6 months. RESULTS: A total of 324 of 393 patients had evaluable neurocognitive data. Changes in cognition function tests from baseline to endpoint were generally small to modest, with improvement noted for most cognitive domains (motor speed, attention/working memory, verbal learning and memory, social cognition, speed of processing, executive functioning). No improvement was noted for visual learning and memory. At baseline, there were modest negative correlations between disorganized thoughts and most cognitive domains; these correlations persisted at 6 months. Other significant negative correlations at 6 months were between speed of processing and PANSS total score, positive symptoms, negative symptoms and uncontrolled hostility (p < 0.05). At 6 months, higher CGAS scores (improved functioning) positively correlated with speed of processing and executive functioning, especially among pali ER responders. CONCLUSIONS: In this large sample of adolescents with schizophrenia, frank cognitive deficits across multiple domains were observed. Treatment with pali ER over 6 months did not worsen neurocognitive functioning and was possibly associated with positive improvement in certain domains.

Prior iterative reconstruction (PIR) to lower radiation dose and preserve radiologist performance for multiphase liver CT: a multi-reader pilot study.

PURPOSE: Prior iterative reconstruction (PIR) spatially registers CT image data from multiple phases of enhancement to reduce image noise. We evaluated PIR in contrast-enhanced multiphase liver CT. METHODS: Patients with archived projection CT data with proven malignant or benign liver lesions, or without lesions, by reference criteria were included. Lower-dose PIR images were reconstructed using validated noise insertion from multiphase CT exams (50% dose in 2 phases, 25% dose in 1 phase). The phase of enhancement most relevant to the diagnostic task was selected for evaluation. Four radiologists reviewed routine-dose and lower-dose PIR images, circumscribing liver lesions and rating confidence for malignancy (0 to 100) and image quality. JAFROC Figures of Merit (FOM) were calculated. RESULTS: 31 patients had 60 liver lesions (28 primary hepatic malignancies, 6 hepatic metastases, 26 benign lesions). Pooled JAFROC FOM for malignancy for routine-dose CT was 0.615 (95% CI 0.464, 0.767) compared to 0.662 for PIR (95% CI 0.527, 0.797). The estimated FOM difference between the routine-dose and lower-dose PIR images was + 0.047 (95% CI - 0.023, + 0.116). Pooled sensitivity/specificity for routine-dose images was 70%/68% compared to 73%/66% for lower-dose PIR. Lower-dose PIR had lower diagnostic image quality (mean 3.8 vs. 4.2, p = 0.0009) and sharpness (mean 2.3 vs. 2.0, p = 0.0071). CONCLUSIONS: PIR is a promising method to reduce radiation dose for multiphase abdominal CT, preserving observer performance despite small reductions in image quality. Further work is warranted.

Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression-TRANSFORM-3.

BACKGROUND: Elderly patients with major depression have a poorer prognosis, are less responsive to treatment, and show greater functional decline compared with younger patients, highlighting the need for effective treatment. METHODS: This phase 3 double-blind study randomized patients with treatment-resistant depression (TRD) ≥65 years (1:1) to flexibly dosed esketamine nasal spray and new oral antidepressant (esketamine/antidepressant) or new oral antidepressant and placebo nasal spray (antidepressant/placebo). The primary endpoint was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to day 28. Analyses included a preplanned analysis by age (65-74 versus ≥75 years) and post-hoc analyses including age at depression onset. RESULTS: For the primary endpoint, the median-unbiased estimate of the treatment difference (95% CI) was -3.6 (-7.20, 0.07); weighted combination test using MMRM analyses z = 1.89, two-sided p = 0.059. Adjusted mean (95% CI) difference for change in MADRS score between treatment groups was -4.9 (-8.96, -0.89; t = -2.4, df = 127; two-sided nominal p = 0.017) for patients 65 to 74 years versus -0.4 (-10.38, 9.50; t = -0.09, two-sided nominal p = 0.930) for those ≥75 years, and -6.1 (-10.33, -1.81; t = -2.8, df = 127; two-sided nominal p = 0.006) for patients with depression onset <55 years and 3.1 (-4.51, 10.80; t = 0.8, two-sided nominal p = 0.407) for those ≥55 years. Patients who rolled over into the long-term open-label study showed continued improvement with esketamine following 4 additional treatment weeks. CONCLUSIONS: Esketamine/antidepressant did not achieve statistical significance for the primary endpoint. Greater differences between treatment arms were seen for younger patients (65-74 years) and patients with earlier onset of depression (<55 years).

Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1).

BACKGROUND: About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression. METHODS: This Phase 3, double-blind, multicenter study enrolled adults with moderate-to-severe depression and nonresponse to ≥2 antidepressants in the current depression episode. Eligible patients (N = 346) were randomized (1:1:1) to twice-weekly nasal spray treatment (esketamine [56 or 84 mg] or placebo) plus a newly initiated, open-label, oral antidepressant taken daily for 4 weeks. The primary efficacy endpoint was change from baseline to day 28 in the Montgomery-Asberg Depression Rating Scale total score, performed by blinded, remote raters. Based on the predefined statistical testing sequence, esketamine 84 mg/antidepressant had to be significant for esketamine 56 mg/antidepressant to be formally tested. RESULTS: Statistical significance was not achieved with esketamine 84 mg/antidepressant compared with antidepressant/placebo (least squares [LS] means difference [95% CI]: -3.2 [-6.88, 0.45]; 2-sided P value = .088). Although esketamine 56 mg/antidepressant could not be formally tested, the LS means difference was -4.1 [-7.67, -0.49] (nominal 2-sided P value = .027). The most common (>20%) adverse events reported for esketamine/antidepressant were nausea, dissociation, dizziness, vertigo, and headache. CONCLUSIONS: Statistical significance was not achieved for the primary endpoint; nevertheless, the treatment effect (Montgomery-Asberg Depression Rating Scale) for both esketamine/antidepressant groups exceeded what has been considered clinically meaningful for approved antidepressants vs placebo. Safety was similar between esketamine/antidepressant groups and no new dose-related safety concerns were identified. This study provides supportive evidence for the safety and efficacy of esketamine nasal spray as a new, rapid-acting antidepressant for patients with treatment-resistant depression. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02417064.