Periocular rejuvenation using a unique non-ablative long-pulse 2940 nm Er:YAG laser.

The periocular region is challenging for cosmetic laser surgeons. Surgery and laser resurfacing have traditionally been used to correct periorbital lines and wrinkles. Although effective, the associated downtime with these methods has made many people reluctant to decide for such treatments. More recently, the non-ablative long-pulse 2940 nm Er:YAG laser is being used to improve the structure and function and hence the appearance of skin in the periorbital region. The objective of this study is to evaluate the safety and efficacy of long-pulse 2940 nm Er:YAG laser for non-ablative treatment of periorbital static wrinkles and skin laxity. This is a prospective analysis of 30 patients treated for periorbital rejuvenation using three sessions of non-ablative long-pulse Er:YAG laser over a 3-month period. All patients were assessed according to Fitzpatrick's classification of periorbital wrinkles to class I, II, or III and were treated with 2940 nm Er:YAG laser using a fluence of 3.75 J/cm2, a repetition rate of 1.7-2 Hz, and with the SMOOTH™ pulse mode (250 ms). The treatment sessions were performed on each patient, 4 weeks apart. Patient improvement was assessed before each laser session as well as at 12 months after the final treatment. Blind photographic evaluations were performed by three independent physicians using unlabeled before and after photos arranged in non-chronological order. Reviewers were asked to determine the before and after photos. Patients were asked to answer a questionnaire measuring satisfaction 4 weeks after each session, and to report any adverse reactions. There was statistically and clinically significant improvement in the Fitzpatrick classification of the periorbital wrinkles. Blinded evaluators correctly identified the before and after photos in all cases. All patients reported mild edema and erythema, which persisted for 1 to 2 days, and superficial peeling of the skin for 4 to 6 days after each laser treatment. No long-term adverse effects were reported. The non-ablative long-pulse 2940 nm Er:YAG laser seems to be a safe and effective treatment for periocular rejuvenation with minimal and tolerable adverse reaction. The improvement attained from the laser sessions was persisting after 1 year denoting the long-term efficacy of the procedure.

Augmentation of learning in schizophrenia by D-serine is related to auditory and frontally-generated biomarkers: A randomized, double-blind, placebo-controlled study.

Auditory cognition is impaired in schizophrenia, and typically engages a complex, distributed, hierarchical network, including both auditory and frontal input. We recently demonstrated proof of principle for the target engagement of an N-methyl-D-aspartate-type glutamate receptor (NMDAR) agonist + auditory targeted remediation (d-serine+AudRem) combination, showing significant improvement in auditory-learning induced plasticity and mismatch negativity. In this secondary analysis, we report on frontal EEG outcomes, assessing for both generalized effects and the mechanism of auditory plasticity. 21 schizophrenia or schizoaffective disorder participants were randomized to three 1x weekly AudRem + double-blind d-serine (100 mg/kg) visits. In AudRem, participants indicated which paired tone was higher in pitch. The focus of this secondary analysis was a frontally (premotor) mediated EEG outcome- event-related desynchronization in the b band (b-ERD), which was shown to be sensitive to AudRem in previous studies. d-Serine+AudRem led to significant improvement in b-ERD power across the retention and motor preparation intervals (F 1,18 =6.0, p=0.025) vs. AudRem alone. b-ERD was significantly related to baseline cognition, but not auditory-learning induced plasticity. The principal finding of this prespecified secondary analysis are that in addition to improving auditory based biomarkers, the d-serine+AudRem combination led to significant improvement in biomarkers thought to represent frontally mediated dysfunction, suggesting potential generalization of effects. Changes in auditory-learning induced plasticity were independent of these frontally mediated biomarkers. Ongoing work will assess whether d-serine+AudRem is sufficient to remediate cognition or whether targeting frontal NMDAR deficits with higher-level remediation may also be required. Trial Registration: NCT03711500.

Dose-Dependent Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia: A Double-Blind, Placebo-Controlled, Randomized, Target Engagement Clinical Trial of the NMDA Glutamate Receptor Agonist d-serine.

BACKGROUND: Patients with schizophrenia show reduced NMDA glutamate receptor-dependent auditory plasticity, which is rate limiting for auditory cognitive remediation (AudRem). We evaluate the utility of behavioral and neurophysiological pharmacodynamic target engagement biomarkers, using a d-serine+AudRem combination. METHODS: Forty-five participants with schizophrenia or schizoaffective disorder were randomized to 3 once-weekly AudRem visits + double-blind d-serine (80, 100, or 120 mg/kg) or placebo in 3 dose cohorts of 12 d-serine and 3 placebo-treated participants each. In AudRem, participants indicated which paired tone was higher in pitch. The primary outcome was plasticity improvement, operationalized as change in pitch threshold between AudRem tones [(test tone Hz - reference tone Hz)/reference tone Hz] between the initial plateau pitch threshold (mean of trials 20-30 of treatment visit 1) to pitch threshold at the end of visit(s). Target engagement was assessed by electroencephalography outcomes, including mismatch negativity (pitch primary). RESULTS: There was a significant overall treatment effect for plasticity improvement (p = .014). Plasticity improvement was largest within the 80 and 100 mg/kg groups (p < .001, d > 0.67), while 120 mg/kg and placebo-treated participants showed nonsignificant within-group changes. Plasticity improvement was seen after a single treatment and was sustained on subsequent treatments. Target engagement was demonstrated by significantly larger mismatch negativity (p = .049, d = 1.0) for the 100 mg/kg dose versus placebo. CONCLUSIONS: Our results demonstrate sufficient proof of principle for continued development of both the d-serine+AudRem combination and our target engagement methodology. The ultimate utility is dependent on the results of an ongoing larger, longer study of the combination for clinically relevant outcomes.

Relationship of Brain Glutamate Response to D-Cycloserine and Lurasidone to Antidepressant Response in Bipolar Depression: A Pilot Study.

N-methyl-D-aspartate glutamate-receptor (NMDAR) antagonists such as ketamine have demonstrated efficacy in both major depressive disorder (MDD) and bipolar disorder depression (BP-D). We have previously reported that reduction in Glx (glutamate + glutamine) in the ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC), measured by proton magnetic resonance spectroscopy (1H MRS) at 3T during a ketamine infusion, mediates the relationship of ketamine dose and blood level to improvement in depression. In the present study, we assessed the impact of D-cycloserine (DCS), an oral NMDAR antagonist combined with lurasidone in BP-D on both glutamate and Glx. Subjects with DSM-V BP-D-I/II and a Montgomery-Asberg Depression Rating Scale (MADRS) score>17, underwent up to three 1H MRS scans. During Scan 1, subjects were randomized to receive double-blind lurasidone 66 mg or placebo. During Scan 2, all subjects received single-blind DCS 950 mg + lurasidone 66 mg, followed by 4 weeks of open label phase of DCS+lurasidone and an optional Scan 3. Five subjects received lurasidone alone and three subjects received placebo for Scan 1. Six subjects received DCS+lurasidone during Scan 2. There was no significant baseline or between treatment-group differences in acute depression improvement or glutamate response. In Scan 2, after a dose of DCS+lurasidone, peak change in glutamate correlated negatively with improvement from baseline MADRS (r = -0.83, p = 0.04). There were no unexpected adverse events. These preliminary pilot results require replication but provide further support for a link between antidepressant effect and a decrease in glutamate by the NMDAR antagonist class of antidepressants.

Double blind, two dose, randomized, placebo-controlled, cross-over clinical trial of the positive allosteric modulator at the alpha7 nicotinic cholinergic receptor AVL-3288 in schizophrenia patients.

Despite their theoretical rationale, nicotinic alpha-7 acetylcholine (nα7) receptor agonists, have largely failed to demonstrate efficacy in placebo-controlled trials in schizophrenia. AVL-3288 is a nα7 positive allosteric modulator (PAM), which is only active in the presence of the endogenous ligand (acetylcholine), and thus theoretically less likely to cause receptor desensitization. We evaluated the efficacy of AVL-3288 in a Phase 1b, randomized, double-blind, placebo-controlled, triple cross-over study. Twenty-four non-smoking, medicated, outpatients with schizophrenia or schizoaffective disorder and a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) ≥62 were randomized. Each subject received 5 days of AVL-3288 (10, 30 mg) and placebo across three separate treatment weeks. The primary outcome measure was the RBANS total scale score, with auditory P50 evoked potential suppression the key target engagement biomarker. Secondary outcome measures include task-based fMRI (RISE task), mismatch negativity, the Scale for the Assessment of Negative Symptoms of Schizophrenia (SANS) and the Brief Psychiatric Rating Scale (BPRS). Twenty-four subjects were randomized and treated without any clinically significant treatment emergent adverse effects. Baseline RBANS (82 ± 17) and BPRS (41 ± 13) scores were consistent with moderate impairment. Primary outcomes were negative, with non-significant worsening for both active groups vs. placebo in the P50 and minimal between group changes on the RBANS. In conclusion, the results did not indicate efficacy of the compound, consistent with most prior results for the nα7 target.

OnTrackNY's learning healthcare system.

Worldwide, early intervention services for young people with recent-onset psychosis have been associated with improvements in outcomes, including reductions in hospitalization, symptoms, and improvements in treatment engagement and work/school participation. States have received federal mental health block grant funding to implement team-based, multi-element, evidence-based early intervention services, now called coordinated specialty care (CSC) in the USA. New York State's CSC program, OnTrackNY, has grown into a 23-site, statewide network, serving over 1800 individuals since its 2013 inception. A state-supported intermediary organization, OnTrackCentral, has overseen the growth of OnTrackNY. OnTrackNY has been committed to quality improvement since its inception. In 2019, OnTrackNY was awarded a regional hub within the National Institute of Mental Health-sponsored Early Psychosis Intervention Network (EPINET). The participation in the national EPINET initiative reframes and expands OnTrackNY's quality improvement activities. The national EPINET initiative aims to develop a learning healthcare system (LHS); OnTrackNY's participation will facilitate the development of infrastructure, including a systematic approach to facilitating stakeholder input and enhancing the data and informatics infrastructure to promote quality improvement. Additionally, this infrastructure will support practice-based research to improve care. The investment of the EPINET network to build regional and national LHSs will accelerate innovations to improve quality of care.

Grant Report on d-Serine Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia †.

We report on the rationale and design of an ongoing NIMH sponsored R61-R33 project in schizophrenia/schizoaffective disorder. This project studies augmenting the efficacy of auditory neuroplasticity cognitive remediation (AudRem) with d-serine, an N-methyl-d-aspartate-type glutamate receptor (NMDAR) glycine-site agonist. We operationalize improved (smaller) thresholds in pitch (frequency) between successive auditory stimuli after AudRem as improved plasticity, and mismatch negativity (MMN) and auditory θ as measures of functional target engagement of both NMDAR agonism and plasticity. Previous studies showed that AudRem alone produces significant, but small cognitive improvements, while d-serine alone improves symptoms and MMN. However, the strongest results for plasticity outcomes (improved pitch thresholds, auditory MMN and θ) were found when combining d-serine and AudRem. AudRem improvements correlated with reading and other auditory cognitive tasks, suggesting plasticity improvements are predictive of functionally relevant outcomes. While d-serine appears to be efficacious for acute AudRem enhancement, the optimal dose remains an open question, as does the ability of combined d-serine + AudRem to produce sustained improvement. In the ongoing R61, 45 schizophrenia patients will be randomized to receive three placebo-controlled, double-blind d-serine + AudRem sessions across three separate 15 subject dose cohorts (80/100/120 mg/kg). Successful completion of the R61 is defined by ≥moderate effect size changes in target engagement and correlation with function, without safety issues. During the three-year R33, we will assess the sustained effects of d-serine + AudRem. In addition to testing a potentially viable treatment, this project will develop a methodology to assess the efficacy of novel NMDAR modulators, using d-serine as a "gold-standard".

Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers.

Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio). The TS-134 trial was a randomized, single-blind, 6-day study of 20 or 60 mg/d TS-134 versus placebo (5:5:2 ratio). Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and symptoms reflected on the Brief Psychiatric Rating Scale (BPRS). Both trials were conducted contemporaneously. 95 healthy volunteers were randomized to POMA and 63 to TS-134. High-dose POMA significantly reduced ketamine-induced BPRS total symptoms within and between-groups (p < 0.01, d = -0.41; p = 0.04, d = -0.44, respectively), but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 led to moderate to large within and between group reductions in both BPRS positive symptoms (p = 0.02, d = -0.36; p = 0.008, d = -0.82, respectively) and dACC pharmacoBOLD (p = 0.004, d = -0.56; p = 0.079, d = -0.50, respectively) using pooled across-study placebo data. High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed, while the low dose of TS-134 showed evidence of symptom reduction and target engagement. These results support further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.

Reflux symptom index versus reflux finding score.

OBJECTIVES: We examined the correlation between the Reflux Symptom Index (RSI) and the Reflux Finding Score (RFS) to determine the laryngeal signs and symptoms that were most significantly correlated. METHODS: Forty randomly selected patients were included in the study. A retrospective chart review was performed for patients who fit the inclusion criteria. Videostroboscopic samples for the study group were reviewed and RFS-rated by 6 experienced raters on 2 different occasions to evaluate the interrater and intrarater reliability. The RSI and the RFS were statistically compared regarding both the total scores and the individual parameters. RESULTS: The RFS ranged from 0 to 20, and the RSI varied from 14 to 38. There was a high agreement between the raters' scores, demonstrating high interrater and intrarater reliability for RFS. Additionally, the RSI and RFS were highly correlated (p < .0001). Hoarseness was highly correlated with vocal fold edema and thick laryngeal mucus (p < .01), and excessive throat clearing correlated significantly with thick endolaryngeal mucus (p < .01). CONCLUSIONS: The study demonstrates a highly significant correlation between the RFS and the RSI.

Postural balance changes in on-duty firefighters: effect of gear and long work shifts.

OBJECTIVE: The objective of this study was to investigate the impact of long work shifts and turnout gear, including the self-contained breathing apparatus (SCBA) on firefighters' postural stability. METHODS: Sixteen firefighters were assessed using a portable forceplate system at the fire station. Postural sway parameters were recorded at the beginning of the work shift and repeated until the work shift ended. RESULTS: Task had the greatest impact on postural stability for all sway parameters. Turnout gear, with and without SCBA, improved postural stability. Postural stability decreased as firefighters spent more time on duty. CONCLUSIONS: Prolonged work shifts may be an important contributor to the high prevalence of slips and falls among firefighters. In all, the results indicate that many aspects of the firefighters' job may adversely impact their postural stability and potentially increase the risk of falling.

Cancer risk among firefighters: a review and meta-analysis of 32 studies.

OBJECTIVE: The objective of this study was to review 32 studies on firefighters and to quantitatively and qualitatively determine the cancer risk using a meta-analysis. METHODS: A comprehensive search of computerized databases and bibliographies from identified articles was performed. Three criteria used to assess the probable, possible, or unlikely risk for 21 cancers included pattern of meta-relative risks, study type, and heterogeneity testing. RESULTS: The findings indicated that firefighters had a probable cancer risk for multiple myeloma with a summary risk estimate (SRE) of 1.53 and 95% confidence interval (CI) of 1.21-1.94, non-Hodgkin lymphoma (SRE = 1.51, 95% CI = 1.31-1.73), and prostate (SRE = 1.28; 95% CI = 1.15-1.43). Testicular cancer was upgraded to probable because it had the highest summary risk estimate (SRE = 2.02; 95% CI = 1.30-3.13). Eight additional cancers were listed as having a "possible" association with firefighting. CONCLUSIONS: Our results confirm previous findings of an elevated metarelative risk for multiple myeloma among firefighters. In addition, a probable association with non-Hodgkin lymphoma, prostate, and testicular cancer was demonstrated.

Cancer education in medical, nursing, and pharmacy schools in Egypt: features applicable to other countries.

The medical and health-related educational system in Egypt has advantages and limitations. Medical education includes a unique system of three-year community-based public health training, but better planning and collaboration among schools could notably increase new physicians' knowledge of cancer detection and prevention. Nurses and pharmacists exert great influence in the provision of health care. Yet, their training includes neither cancer education nor information about prevention. The medical and health-related educational system in Egypt has many limitations, but it has the structure and inherent ability to achieve cancer education goals.