Audiometric assessment of hearing loss sustained during military service.

An analysis is presented of the audiograms, obtained using Telephonics TDH39 headphones (Huntington, NY), of 80 men claiming compensation for noise-induced hearing loss (NIHL) sustained during military service. A comparison with an independent database of audiograms collected using other headphones suggested that no adjustment was needed to the hearing threshold levels (HTLs) at 6 kHz to allow for the use of TDH39 headphones. The method of Moore [(2020). J. Acoust. Soc. Am. 148, 884-894] for diagnosing military noise-induced hearing loss (M-NIHL) gave a positive diagnosis for 92.5% of right ears and 97.5% of left ears. The mean HTLs were maximal and similar at 4, 6, and 8 kHz but with considerable individual variability. A comparison with age-expected HTLs showed that M-NIHL was typically greatest at 3, 4, 6, or 8 kHz but with considerable individual variability. M-NIHL values were positive from 0.5 to 8 kHz. The HTLs were significantly higher for the left than for the right ears, but the asymmetry varied across individuals and could usually be ascribed to specific features of the noise exposure. The asymmetry existed over the range from 0.5 to 8 kHz, supporting the idea that M-NIHL occurs over a wide frequency range. Tinnitus was reported by 76 of the 80 men.

Performance of Emergency Medical Service Providers in Pediatric and Adult Simulation of Unstable Supraventricular Tachycardia.

OBJECTIVE: The aim of the study was to compare emergency medical service resuscitation of pediatric and adult high-fidelity manikins in unstable supraventricular tachycardia. The primary objective was time to cardioversion. The secondary objective was to assess if the cardioversion was synchronized at the correct dosage for the manikin's weight. METHODS: Emergency medical service providers were voluntarily enrolled as part of an emergency medical service training program. Participants were randomized to either a pediatric or adult resuscitation as their study scenario. They then completed the second resuscitation as part of the training program. Participants completed presurvey and postsurvey. Resuscitations were videotaped and analyzed by a blinded reviewer. The study was powered to detect a 60-second difference in performance between pediatric and adult scenarios with a ß of 0.8 and 2-tailed α of 0.05 using an independent-samples t test. RESULTS: A total of 37 participants were enrolled. Participants in the pediatric arm had a longer mean time to cardioversion, but the difference was not statistically significant. The mean delay to cardioversion in the pediatric scenario was 34 seconds (197 vs 163 seconds; difference 95% confidence interval [CI], -5 to 73 seconds; P = 0.09). There was no significant difference in the percentage of participants who administered a correct dose (32% vs 50%; difference 95% CI, -50% to 13%; P = 0.75) or regarding synchronization of cardioversion (74% vs 83%; difference 95% CI, -36% to 17%; P = 0.42). CONCLUSIONS: Emergency medical service providers did not have a significant difference in time to cardioversion between pediatric and adult unstable supraventricular tachycardia simulations.

Nonlinear Evolution of the AdS_{4} Superradiant Instability.

The superradiant instability of rotating black holes with negative cosmological constant is studied by numerically solving the full (3+1)-dimensional Einstein equations. We find evidence for an epoch dominated by a solution with a single helical Killing vector and a multistage process with distinct superradiant instabilities.

Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson's disease: a dose-finding study.

In advanced stages of Parkinson's disease, serotonergic terminals take up L-DOPA and convert it to dopamine. Abnormally released dopamine may participate in the development of L-DOPA-induced dyskinesias. Simultaneous activation of 5-HT1A and 5-HT1B receptors effectively blocks L-DOPA-induced dyskinesias in animal models of dopamine depletion, justifying a clinical study with eltoprazine, a 5-HT1A/B receptor agonist, against L-DOPA-induced dyskinesias in patients with Parkinson's disease. A double-blind, randomized, placebo-controlled and dose-finding phase I/IIa study was conducted. Single oral treatment with placebo or eltoprazine, at 2.5, 5 and 7.5 mg, was tested in combination with a suprathreshold dose of L-DOPA (Sinemet®) in 22 patients with Parkinson's disease (16 male/six female; 66.6 ± 8.8 years old) with L-DOPA-induced dyskinesias. A Wilcoxon Signed Ranked Test was used to compare each eltoprazine dose level to paired randomized placebo on the prespecified primary efficacy variables; area under the curve scores on Clinical Dyskinesia Rating Scale for 3 h post-dose and maximum change of Unified Parkinson's Disease Rating Scale part III for 3 h post-dose. Secondary objectives included effects on maximum Clinical Dyskinesia Rating Scale score, area under the curve of Rush Dyskinesia Rating Scale score for 3 h post-dose, mood parameters measured by Hospital Anxiety Depression Scale and Montgomery Asberg Depression Rating Scale along with the pharmacokinetics, safety and tolerability profile of eltoprazine. A mixed model repeated measures was used for post hoc analyses of the area under the curve and peak Clinical Dyskinesia Rating Scale scores. It was found that serum concentrations of eltoprazine increased in a dose-proportional manner. Following levodopa challenge, 5 mg eltoprazine caused a significant reduction of L-DOPA-induced dyskinesias on area under the curves of Clinical Dyskinesia Rating Scale [-1.02(1.49); P = 0.004] and Rush Dyskinesia Rating Scale [-0.15(0.23); P = 0.003]; and maximum Clinical Dyskinesia Rating Scale score [-1.14(1.59); P = 0.005]. The post hoc analysis confirmed these results and also showed an antidyskinetic effect of 7.5 mg eltoprazine. Unified Parkinson's Disease Rating Scale part III scores did not differ between the placebo and eltoprazine treatments. The most frequent adverse effects after eltoprazine were nausea and dizziness. It can be concluded that a single dose, oral treatment with eltoprazine has beneficial antidyskinetic effects without altering normal motor responses to L-DOPA. All doses of eltoprazine were well tolerated, with no major adverse effects. Eltoprazine has a favourable risk-benefit and pharmacokinetic profile in patients with Parkinson's disease. The data support further clinical studies with chronic oral eltoprazine to treat l-DOPA-induced-dyskinesias.

Disparities and Trends in Migraine Management in Pediatric Emergency Departments, 2009-19.

OBJECTIVE: To assess the variation in migraine management over time across US children's hospitals and to identify factors associated with disparities in management. METHODS: We conducted a retrospective study of 32 hospitals in the Pediatric Health Information System from 2009 to 2019. We included children 7 to 21 years old with primary ICD-9 or ICD-10 diagnosis codes for migraine headache. We surveyed hospitals to assess for clinical guideline presence. We assessed medication use trends over time. To examine differences in medication and advanced head imaging use by patient characteristics and presence of clinical guideline, we performed multivariable logistic regression analyses reporting adjusted odds ratios (aOR) with 95% confidence intervals (CI). RESULTS: We identified 112,077 eligible visits. Opioid use decreased over time, while nonopioid analgesic, dopamine antagonist, and diphenhydramine use increased. Multivariable analysis for opioids revealed increased odds of use for those 14 to 17 (aOR 1.19; 95% CI, 1.06, 1.34) and 18 to 21 years old (aOR 1.69; CI, 1.37, 2.08), and clinical guideline presence had decreased odds (aOR 0.64; CI, 0.48, 0.84). For head computed tomography, increased odds of use were reported for Hispanic ethnicity (aOR 1.15; CI, 1.06, 1.24) and decreased odds for 14 to 17 years (aOR 0.85; CI, 0.80, 0.90), 18 to 21 years (aOR 0.87; CI, 0.77, 0.98), and female sex (aOR 0.74; CI, 0.70, 0.79). CONCLUSIONS: Opioid use decreased while other medications increased over time. Medication and imaging differed by demographic characteristics. Opioid use was less likely in hospitals with clinical guidelines. Standardization in management may decrease care disparities and variability.

Guidelines for Diagnosing and Quantifying Noise-Induced Hearing Loss.

This paper makes recommendations for the diagnosis and quantification of noise-induced hearing loss (NIHL) in a medico-legal context. A distinction is made between NIHL produced by: steady broadband noise, as occurs in some factories; more impulsive factory sounds, such as hammering; noise exposure during military service, which can involve very high peak sound levels; and exposure to very intense tones. It is argued that existing diagnostic methods, which were primarily developed to deal with NIHL produced by steady broadband noise, are not adequate for the diagnosis of NIHL produced by different types of exposures. Furthermore, some existing diagnostic methods are based on now-obsolete standards, and make unrealistic assumptions. Diagnostic methods are proposed for each of the types of noise exposure considered. It is recommended that quantification of NIHL for all types of exposures is based on comparison of the measured hearing threshold levels with the age-associated hearing levels (AAHLs) for a non-noise exposed population, as specified in ISO 7029 (2017), usually using the 50th percentile, but using another percentile if there are good reasons for doing so. When audiograms are available both soon after the end of military service and some time afterwards, the most recent audiogram should be used for diagnosis and quantification, since this reflects any effect of the noise exposure on the subsequent progression of hearing loss. It is recommended that the overall NIHL for each ear be quantified as the average NIHL across the frequencies 1, 2, and 4 kHz.

Does Exposure to Noise During Military Service Affect the Progression of Hearing Loss with Increasing Age?

It is traditionally believed that the effects of exposure to noise cease once the exposure itself has ceased. If this is the case, exposure to noise relatively early in life, for example during military service, should not affect the subsequent progression of hearing loss. However, recent data from studies using animals suggest that noise exposure can accelerate the subsequent progression of hearing loss. This paper presents new longitudinal data obtained from 29 former male military personnel. Audiograms obtained at the end of military service were compared with those obtained at least five years later. Rates of change of hearing threshold level (HTL) in dB/year were compared with those expected from ISO7029 (2017) for men at the 50th percentile. The results are consistent with the hypothesis that noise exposure during military service accelerates the progression of hearing loss for frequencies where the hearing loss is absent or mild at the end of military service, by about 1.7 dB/year on average for frequencies from 3 to 8 kHz, but has no effect on or slows the progression of hearing loss for frequencies where the hearing loss exceeds about 50 dB. Acceleration appears to occur over a wide frequency range, including 1 kHz. There remains a need for further longitudinal studies using larger sample sizes. Longitudinal studies are also needed to establish whether exposure to other types of sounds, for example at rock concerts or from work in heavy industries, affects the subsequent progression of hearing loss.

The effect of a structured ECPR protocol aided by specific simulation training in a quaternary ECMO centre: A retrospective pre-post study.

Background: There is limited literature exploring the relationship between simulation training and extracorporeal cardiopulmonary resuscitation (ECPR) outcomes. We examined whether there was an association between the implementation of an in situ simulation training program and ECPR utilisation, time to extracorporeal membrane oxygenation (ECMO), and neurologically intact survival. Methods: In this retrospective pre-post study of in-hospital cardiac arrests (IHCA) and out-of-hospital cardiac arrests (OHCA), we analysed data for all patients recorded as receiving ECPR from September 2009 to December 2020 at our institution, relative to the implementation of an in situ ECPR simulation training program and a standardised procedure for high-quality ECPR. The primary outcome was Cerebral Performance Category (CPC) 1 or 2 at hospital discharge. Results: There were 27 patients in the pre-intervention period and 39 patients in the post-intervention period. The median ECPR rate per year was 2 pre-intervention and 7 post-intervention (p = 0.073). There was an association between the implementation of the program and decreased median time from OHCA to ECMO flow, from 87 (IQR 78-95) minutes pre-intervention to 70 (IQR 69-72) minutes post-intervention (p = 0.002). Median time from IHCA to ECMO flow was 40 (IQR 20-75) minutes pre-intervention and 28 (IQR 16-41) minutes post-intervention (p = 0.134). Survival with CPC 1 or 2 was 7/27 (25.9%) pre-intervention and 15/39 (38.5%) post-intervention (p = 0.288). Conclusion: We observed an association between the implementation of an ECPR-specific simulation program and decreased time from OHCA to ECMO flow. There was no association between the implementation of the program and neurologically intact survival at hospital discharge.

RG3487, a novel nicotinic α7 receptor partial agonist, improves cognition and sensorimotor gating in rodents.

Neuronal nicotinic α7 acetylcholine receptors (α7nAChRs) are expressed primarily in the brain and are implicated in modulating many cognitive functions (e.g., attention, working and episodic memory). Not surprisingly, much effort has been committed to the development of molecules acting at α7nAChRs as potential therapies for a variety of central nervous system diseases (e.g., Alzheimer's). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide hydrochloride (RG3487) binds potently to the human α7nAChR (K(i) = 6 nM), in which it acts as a partial agonist (63-69% of acetylcholine) as assessed by whole-cell patch-clamp recordings in both oocytes and QM7 cell lines. RG3487 activates human α7nAChRs with an EC(50) of 0.8 µM (oocytes) and 7.7 µM (QM7 cells). RG3487 also exhibits antagonist properties at the serotonin 3 receptor [IC(50) = 2.8 nM (oocytes), 32.7 nM (N1E-115 cells)]. In vivo, RG3487 improved object recognition memory in rats after acute [minimally effective dose (MED) 1.0 mg/kg p.o.] or repeated (10 day) administration at brain and plasma concentrations in the low-nanomolar range. Spatial learning deficits in age-impaired rats were reversed after RG3487 administration (MED: 0.03 mg/kg i.p.) as evaluated in the Morris water maze task. In the prepulse inhibition (PPI) of startle model of sensorimotor gating, RG3487 improved apomorphine-induced deficits in PPI performance (MED: 0.03 mg/kg i.p.) and reversed phencyclidine-induced impairments in an attentional set-shifting model of executive function (MED: ≤0.03 mg/kg i.p.). Cumulative evidence from these studies indicates RG3487 is a novel and potent α7nAChR partial agonist that improves cognitive performance and sensorimotor gating.

Prospective observational study of mechanical cardiopulmonary resuscitation, extracorporeal membrane oxygenation and early reperfusion for refractory cardiac arrest in Sydney: the 2CHEER study.

BACKGROUND: Patients with prolonged cardiac arrest that is not responsive to conventional cardiopulmonary resuscitation have poor outcomes. The use of extracorporeal membrane oxygenation (ECMO) in refractory cardiac arrest has shown promising results in carefully selected cases. We sought to validate the results from an earlier extracorporeal cardiopulmonary resuscitation (ECPR) study (the CHEER trial). METHODS: Prospective, consecutive patients with refractory in-hospital (IHCA) or out-of-hospital cardiac arrest (OHCA) who met predefined inclusion criteria received protocolised care, including mechanical cardiopulmonary resuscitation, initiation of ECMO, and early coronary angiography (if an acute coronary syndrome was suspected). RESULTS: Twenty-five patients were enrolled in the study (11 OHCA, 14 IHCA); the median age was 57 years (interquartile range [IQR], 39-65 years), and 17 patients (68%) were male. ECMO was established in all patients, with a median time from arrest to ECMO support of 57 minutes (IQR, 38-73 min). Percutaneous coronary intervention was performed on 18 patients (72%). The median duration of ECMO support was 52 hours (IQR, 24-108 h). Survival to hospital discharge with favourable neurological recovery occurred in 11/25 patients (44%, of which 72% had IHCA and 27% had OHCA). When adjusting for lactate, arrest to ECMO flow time was predictive of survival (odds ratio, 0.904; P = 0.035). CONCLUSION: ECMO for refractory cardiac arrest shows promising survival rates if protocolised care is applied in conjunction with predefined selection criteria.

Effect of R3487/MEM3454, a novel nicotinic alpha7 receptor partial agonist and 5-HT3 antagonist on sustained attention in rats.

It is well established that nicotinic systems in the brain are critically involved in attentional processes in both animals and humans. The current study assessed the effects of a novel nicotinic alpha7 receptor partial agonist and 5-HT3 antagonist, R3487/MEM3454 (also referred to as R3487 or MEM 3454) on sustained attention in rats performing an operant visual signal detection task. The effects of R3487/MEM3454 were compared to those of the acetylcholinesterase inhibitor/nicotinic alpha7 allosteric positive modulator galanthamine. Adult female Sprague-Dawley rats were injected subcutaneously with R3487/MEM3454 (0.03, 0.1, 0.15, 0.3 and 0.6 mg/kg), galanthamine (0.25, 0.5, 1, 2 mg/kg) or vehicle 30 min before the attentional test. In the second study, the time-dependent effects of R3487/MEM3454 were assessed by injecting the compound (0.6 mg/kg, s.c.) at different pretreatment intervals (30, 60 or 90 min) before the start of the attentional task. Our results show a significant dose-effect for R3487/MEM3454 on percent hit accuracy performance without any significant alteration on percent correct rejection performance. In the time-dependent test, R3487/MEM3454 significantly increased the percent hit accuracy performance when animals were injected 60 min before the start of the attentional task. Administration of galanthamine failed to significantly increase percent hit accuracy performance and increasing the dose of galanthamine produced a decrease in percent correct rejection performance. The present findings with R3487/MEM3454 suggest that nicotinic alpha7 receptors and/or 5-HT3 receptors may play an important role in modulating sustained attention and that R3487/MEM3454 may have therapeutic potential in improving sustained attention in humans.

The origin of bronchial foreign bodies: a retrospective study and literature review.

Nasal foreign bodies are managed as an emergency for the risk of aspiration, yet it is not clear what proportion of bronchial foreign bodies actually originate in the nose. The aim of this study was to identify the origin of bronchial foreign bodies and estimate the risk of a nasal foreign body becoming impacted in the bronchial tree. We present a retrospective study of suspected bronchial foreign body cases at Addenbrooke's Hospital in Cambridge, UK, who underwent a bronchoscopy between 2002 and 2007. We further compare our experience with a literature review on bronchial and nasal foreign bodies to highlight important differences between these distinct clinical problems. Our experience shows that all cases of proven foreign body at bronchoscopy had ingested the foreign body orally. We could find only one case of a nasal foreign body in the literature that had been ingested during its removal, but no cases specifically entering the tracheo-bronchial tree. We therefore conclude that bronchial foreign bodies have their origin almost invariably in the mouth and the risk of a nasal foreign body entering the bronchial tree is negligible (<0.06%).

Extracorporeal cardiopulmonary resuscitation for refractory cardiac arrest: A multicentre experience.

AIM: To describe the ECPR experience of two Australian ECMO centres, with regards to survival and neurological outcome, their predictors and complications. METHODS: Retrospective observational study of prospectively collected data on all patients who underwent extracorporeal cardiopulmonary resuscitation (ECPR) at two academic ECMO referral centres in Sydney, Australia. MEASUREMENTS AND MAIN RESULTS: Thirty-seven patients underwent ECPR, 25 (68%) were for in-hospital cardiac arrests. Median age was 54 (IQR 47-58), 27 (73%) were male. Initial rhythm was ventricular fibrillation or pulseless ventricular tachycardia in 20 patients (54%), pulseless electrical activity (n=14, 38%), and asystole (n=3, 8%). 27 (73%) arrests were witnessed and 30 (81%) patients received bystander CPR. Median time from arrest to initiation of ECMO flow was 45min (IQR 30-70), and the median time on ECMO was 3days (IQR 1-6). Angiography was performed in 54% of patients, and 27% required subsequent coronary intervention (stenting or balloon angioplasty 24%). A total of 13 patients (35%) survived to hospital discharge (IHCA 33% vs. OHCA 37%). All survivors were discharged with favourable neurological outcome (Cerebral Performance Category 1 or 2). Pre-ECMO lactate level was predictive of mortality OR 1.35 (1.06-1.73, p=0.016). CONCLUSIONS: In selected patients with refractory cardiac arrest, ECPR may provide temporary support as a bridge to intervention or recovery. We report favourable survival and neurological outcomes in one third of patients and pre-ECMO lactate levels predictive of mortality. Further studies are required to determine optimum selection criteria for ECPR.

Effects of cannabinoid receptor ligands on psychosis-relevant behavior models in the rat.

RATIONALE: Marijuana is known to have psychotropic effects in humans. In this study, we used rat models of sensorimotor gating, hyperactivity and stereotypy to explore whether CB(1) receptor stimulation or blockade induces behavioral changes consistent with psychotomimetic or antipsychotic agents, respectively. OBJECTIVES: We determined whether (a) the cannabinoid agonist CP 55940 decreased pre-pulse inhibition (PPI) as might be expected from a psychotomimetic agent, and (b) the selective CB(1) receptor antagonist, SR 141716A, had any effect on PPI on its own or following disruptions by psychotomimetic agents. In addition, we investigated the effects of SR 141716A on elevated levels of hyperactivity and stereotypy elicited by d-amphetamine. METHODS: These studies were conducted in rats using standard methodologies for determination of PPI following acoustic stimuli, and d-amphetamine-induced hyperactivity and stereotypies. RESULTS: Decreased startle responses to 120 dB stimuli were observed in rats treated with CP 55940 (0.1 mg/kg IP) in the absence and presence of a 73 dB pre-pulse. These effects were reversed by SR 141716A (5 and 10 mg/kg, respectively). SR 141716A (0.1, 5, 10 mg/kg) had no effect on PPI on its own or following disruptions by apomorphine, d-amphetamine or MK-801. Conversely, in separate experiments different antipsychotic agents reversed disruptions in PPI induced by d-amphetamine (haloperidol), apomorphine (haloperidol or clozapine) or MK-801 (clozapine or olanzapine). In addition, unlike haloperidol, SR 141716A (5 mg/kg) did not reverse d-amphetamine-mediated increases in hyperactivity or stereotypy. CONCLUSIONS: The CP 55940-mediated decreases in startle amplitude confound assessment of the effects of CB(1) receptor activation on PPI. The failure of SR 141716A to reverse disruptions in PPI, hyperactivity or stereotypy induced by non-cannabinoid psychotomimetic agents suggests that blockade of the CB(1) receptor on its own is not sufficient for antipsychotic therapy.

A randomized, placebo-controlled study investigating the nicotinic α7 agonist, RG3487, for cognitive deficits in schizophrenia.

Effective treatments for cognitive impairment associated with schizophrenia (CIAS) remain an unmet need. Nicotinic α7 receptor agonists may be effective in CIAS. This 8-week (week 1, inpatient; weeks 2-8, outpatient), double-blind, randomized study used Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) guidelines to investigate the nicotinic α7 partial agonist RG3487 (formerly MEM3454) in CIAS; 215 patients with chronic stable schizophrenia received placebo or RG3487 (5, 15, or 50 mg) added to ongoing treatment with risperidone, paliperidone, or aripiprazole. Primary end point was baseline to week 8 change in MATRICS Consensus Cognitive Battery (MCCB) composite t-score. Secondary outcomes were change in MCCB domain and negative symptom assessment (NSA) scores. The study did not allow for evaluation of nonsmokers. Each RG3487 dose was evaluated using a mixed-effects model repeated measures approach. Mean (SD) baseline MCCB composite t-score was 28.3 (12.0). No significant effect on MCCB composite t-scores was observed with RG3487 (adjusted mean difference (SE) vs placebo: 5 mg: 0.11 (1.39); 15 mg: -1.95 (1.39); 50 mg: -1.13 (1.37); p = 0.2-0.9). RG3487 did not improve MCCB domain scores. In a post hoc analysis of patients with moderate negative symptoms, 5 and 50 mg RG3487 vs placebo significantly improved NSA total (-4.45 (p = 0.04) and -4.75 (p = 0.02), respectively) and global (-0.39 (p = 0.04) and -0.55 (p = 0.003), respectively) scores. The MCCB did not lead to higher than expected patient withdrawal. RG3487 was generally well tolerated. In patients with stable schizophrenia, RG3487 did not improve cognitive deficits, as assessed by the MCCB; however, in patients with moderate negative symptoms, a post hoc analysis revealed significant improvement of negative symptoms.

NAAG peptidase inhibitor improves motor function and reduces cognitive dysfunction in a model of TBI with secondary hypoxia.

Immediately following traumatic brain injury (TBI) and TBI with hypoxia, there is a rapid and pathophysiological increase in extracellular glutamate, subsequent neuronal damage and ultimately diminished motor and cognitive function. N-acetyl-aspartyl glutamate (NAAG), a prevalent neuropeptide in the CNS, is co-released with glutamate, binds to the presynaptic group II metabotropic glutamate receptor subtype 3 (mGluR3) and suppresses glutamate release. However, the catalytic enzyme glutamate carboxypeptidase II (GCP II) rapidly hydrolyzes NAAG into NAA and glutamate. Inhibition of the GCP II enzyme with NAAG peptidase inhibitors reduces the concentration of glutamate both by increasing the duration of NAAG activity on mGluR3 and by reducing degradation into NAA and glutamate resulting in reduced cell death in models of TBI and TBI with hypoxia. In the following study, rats were administered the NAAG peptidase inhibitor PGI-02776 (10mg/kg) 30 min following TBI combined with a hypoxic second insult. Over the two weeks following injury, PGI-02776-treated rats had significantly improved motor function as measured by increased duration on the rota-rod and a trend toward improved performance on the beam walk. Furthermore, two weeks post-injury, PGI-02776-treated animals had a significant decrease in latency to find the target platform in the Morris water maze as compared to vehicle-treated animals. These findings demonstrate that the application of NAAG peptidase inhibitors can reduce the deleterious motor and cognitive effects of TBI combined with a second hypoxic insult in the weeks following injury.

Predictors of parent satisfaction in pediatric laceration repair.

OBJECTIVES: Patient and parent satisfaction are important measures of quality of care. Data are lacking regarding satisfaction with emergency procedures, including laceration repair. The objective was to define the elements of care that are important to parents during a pediatric laceration repair and to determine the predictors of excellent parent satisfaction. METHODS: This was a cross-sectional observational study of a convenience sample of patients younger than 18 years of age presenting for laceration repair to an urban tertiary care children's hospital emergency department (ED). At the end of the ED visit, parents completed a survey developed for this study assessing ratings of their experience and their perception of how their child experienced the repair. Exploratory factor analysis was used to derive the factors comprising parents' perception of the laceration repair process. A separate factor analysis was performed for the 0- to 4-years age subgroup. Multivariate logistic regression was used to determine which of these factors predicted excellent parent satisfaction with the visit, and also satisfaction with the procedure itself, adjusting for sociodemographic factors. RESULTS: A total of 408 parents returned completed surveys (response rate=76%). Factor analysis revealed that three factors provided a summary of the 16 survey items. They were labeled "provider performance,""anxiety and pain," and "cosmetic appearance," based on factor loading patterns. Provider performance was the only predictor of satisfaction with the visit (adjusted odds ratio [OR]=11.6; 95% confidence interval [CI]=6.2 to 21.6). Provider performance (adjusted OR=4.7; 95% CI=3.1 to 7.2) and cosmetic appearance (adjusted OR 2.7; 95% CI=1.7 to 4.2) predicted satisfaction with the procedure. Anxiety and pain did not predict either outcome. CONCLUSIONS: Provider performance, which comprises the elements of physician communication, caring attitude, confidence, and hygiene, is the strongest predictor of excellent parent satisfaction for pediatric patients with ED visits for laceration repair.

NAAG peptidase inhibitor reduces cellular damage in a model of TBI with secondary hypoxia.

Traumatic brain injury (TBI) leads to a rapid and excessive glutamate elevation in the extracellular milieu, resulting in neuronal degeneration and astrocyte damage. Posttraumatic hypoxia is a clinically relevant secondary insult that increases the magnitude and duration of glutamate release following TBI. N-acetyl-aspartyl glutamate (NAAG), a prevalent neuropeptide in the CNS, suppresses presynaptic glutamate release by its action at the mGluR3 (a group II metabotropic glutamate receptor). However, extracellular NAAG is rapidly converted into NAA and glutamate by the catalytic enzyme glutamate carboxypeptidase II (GCPII) reducing presynaptic inhibition. We previously reported that the GCPII inhibitor ZJ-43 and its prodrug di-ester PGI-02776 reduce the deleterious effects of excessive extracellular glutamate when injected systemically within the first 30 min following injury. We now report that PGI-02776 (10mg/kg) is neuroprotective when administered 30 min post-injury in a model of TBI plus 30 min of hypoxia (FiO(2)=11%). 24h following TBI with hypoxia, significant increases in neuronal cell death in the CA1, CA2/3, CA3c, hilus and dentate gyrus were observed in the ipsilateral hippocampus. Additionally, there was a significant reduction in the number of astrocytes in the ipsilateral CA1, CA2/3 and in the CA3c/hilus/dentate gyrus. Administration of PGI-02776 immediately following the cessation of hypoxia significantly reduced neuronal and astrocytic cell death across all regions of the hippocampus. These findings indicate that NAAG peptidase inhibitors administered post-injury can significantly reduce the deleterious effects of TBI combined with a secondary hypoxic insult.

Chemistry and behavioral studies identify chiral cyclopropanes as selective α4ß2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile.

Despite their discovery in the early 20th century and intensive study over the last 20 years, nicotinic acetylcholine receptors (nAChRs) are still far from being well understood. Only a few chemical entities targeting nAChRs are currently undergoing clinical trials, and even fewer have reached the marketplace. In our efforts to discover novel and truly selective nAChR ligands, we designed and synthesized a series of chiral cyclopropane-containing α4ß2-specific ligands that display low nanomolar binding affinities and excellent subtype selectivity while acting as partial agonists at α4ß2-nAChRs. Their favorable antidepressant-like properties were demonstrated in the classical mouse forced swim test. Preliminary ADMET studies and broad screening toward other common neurotransmitter receptors were also carried out to further evaluate their safety profile and eliminate their potential off-target activity. These highly potent cyclopropane ligands possess superior subtype selectivity compared to other α4ß2-nAChR agonists reported to date, including the marketed drug varenicline, and therefore may fully satisfy the crucial prerequisite for avoiding adverse side effects. These novel chemical entities could potentially be advanced to the clinic as new drug candidates for treating depression.