Inhibition of post-lanosterol biosynthesis by fentanyl: potential implications for Fetal Fentanyl Syndrome (FFS).

A recent study discovered a novel, complex developmental disability syndrome, most likely caused by maternal fentanyl use disorder. This Fetal Fentanyl Syndrome (FFS) is biochemically characterized by elevated 7-dehydrocholesterol (7-DHC) levels in neonates, raising the question if fentanyl inhibition of the dehydrocholesterol reductase 7 (DHCR7) enzyme is causal for the emergence of the pathophysiology and phenotypic features of FFS. To test this hypothesis, we undertook a series of experiments on Neuro2a cells, primary mouse neuronal and astrocytic cultures, and human dermal fibroblasts (HDFs) with DHCR7+/+ and DHCR7+/- genotype. Our results revealed that in vitro exposure to fentanyl disrupted sterol biosynthesis across all four in vitro models. The sterol biosynthesis disruption by fentanyl was complex, and encompassed the majority of post-lanosterol intermediates, including elevated 7-DHC and decreased desmosterol (DES) levels across all investigated models. The overall findings suggested that maternal fentanyl use in the context of an opioid use disorder leads to FFS in the developing fetus through a strong disruption of the whole post-lanosterol pathway that is more complex than a simple DHCR7 inhibition. In follow-up experiments we found that heterozygous DHCR7+/- HDFs were significantly more susceptible to the sterol biosynthesis inhibitory effects of fentanyl than wild-type DHCR7+/+ fibroblasts. These data suggest that DHCR7+/- heterozygosity of mother and/or developing child (and potentially other sterol biosynthesis genes), when combined with maternal fentanyl use disorder, might be a significant contributory factor to the emergence of FFS in the exposed offspring. In a broader context, we believe that evaluation of new and existing medications for their effects on sterol biosynthesis should be an essential consideration during drug safety determinations, especially in pregnancy.

GPCR-dependent biasing of GIRK channel signaling dynamics by RGS6 in mouse sinoatrial nodal cells.

How G protein-coupled receptors (GPCRs) evoke specific biological outcomes while utilizing a limited array of G proteins and effectors is poorly understood, particularly in native cell systems. Here, we examined signaling evoked by muscarinic (M2R) and adenosine (A1R) receptor activation in the mouse sinoatrial node (SAN), the cardiac pacemaker. M2R and A1R activate a shared pool of cardiac G protein-gated inwardly rectifying K+ (GIRK) channels in SAN cells from adult mice, but A1R-GIRK responses are smaller and slower than M2R-GIRK responses. Recordings from mice lacking Regulator of G protein Signaling 6 (RGS6) revealed that RGS6 exerts a GPCR-dependent influence on GIRK-dependent signaling in SAN cells, suppressing M2R-GIRK coupling efficiency and kinetics and A1R-GIRK signaling amplitude. Fast kinetic bioluminescence resonance energy transfer assays in transfected HEK cells showed that RGS6 prefers Gαo over Gαi as a substrate for its catalytic activity and that M2R signals preferentially via Gαo, while A1R does not discriminate between inhibitory G protein isoforms. The impact of atrial/SAN-selective ablation of Gαo or Gαi2 was consistent with these findings. Gαi2 ablation had minimal impact on M2R-GIRK and A1R-GIRK signaling in SAN cells. In contrast, Gαo ablation decreased the amplitude and slowed the kinetics of M2R-GIRK responses, while enhancing the sensitivity and prolonging the deactivation rate of A1R-GIRK signaling. Collectively, our data show that differences in GPCR-G protein coupling preferences, and the Gαo substrate preference of RGS6, shape A1R- and M2R-GIRK signaling dynamics in mouse SAN cells.

Modeling the Design Characteristics of Woven Textile Electrodes for long-Term ECG Monitoring.

An electrocardiograph records the periodic voltage generated by the heart over time. There is growing demand to continuously monitor the ECG for proactive health care and human performance optimization. To meet this demand, new conductive textile electrodes are being developed which offer an attractive alternative to adhesive gel electrodes but they come with their own challenges. The key challenge with textile electrodes is that the relationship between the manufacturing parameters and the ECG measurement is not well understood, making design an iterative process without the ability to prospectively develop woven electrodes with optimized performance. Here we address this challenge by applying the traditional skin-electrode interface circuit model to woven electrodes by constructing a parameterized model of the ECG system. Then the unknown parameters of the system are solved for with an iterative MATLAB optimizer using measured data captured with the woven electrodes. The results of this novel analysis confirm that yarn conductivity and total conductive area reduce skin electrode impedance. The results also indicate that electrode skin pressure and moisture require further investigation. By closing this gap in development, textile electrodes can be better designed and manufactured to meet the demands of long-term ECG capture.

Natural Scene Virtual Reality as a Behavioral Health Countermeasure in Isolated, Confined, and Extreme Environments: Three Isolated, Confined, Extreme Analog Case Studies.

INTRODUCTION: Isolated, confined, extreme (ICE) environments are accompanied by a host of stress-inducing circumstances: operational pressure, interpersonal dynamics, limited communication with friends and family, and environmental hazards. We evaluated the effectiveness of attention-restoration-therapy-based immersive Virtual Reality (VR) in three ICE environments: the Canadian Forces Station-Alert (CFS Alert), the 12-month HI-SEAS IV expedition, and the 8-month HI-SEAS V expedition. METHODS: Thirty-one individuals (29 male, 2 female) at CFS Alert, and 12 total crewmembers (7 male, 5 female, six crewmembers per sessions) at HI-SEAS participated. All participants viewed immersive VR scenes, but scene content varied by deployment. Data collection included pre- and post-intervention surveys and semi-structured post-mission interviews. Survey data were analyzed by scene content within each analog using nonparametric approaches. RESULTS: Acceptability and desirability of the VR content varied significantly by ICE analog, as well as by participants within a given analog. The two initial exploratory protocols enabled a more directed study in HI-SEAS V to identify the importance of differences in scene content. DISCUSSION: Use and perceived utility of the VR varied considerably across participants, indicating that psychological support needs to be individualized. Overall, natural scene VR was broadly considered restorative, but after long periods of isolation, dynamic and familiar scenes including those with people were also appealing. Immersive, nature-based VR was highly valued by some, but not all participants, suggesting that this intervention tool holds promise for use in ICE settings but needs to be tailored to the setting and individual.

Estimation of Subjectively Reported Trust, Mental Workload, and Situation Awareness Using Unobtrusive Measures.

OBJECTIVE: We use a set of unobtrusive measures to estimate subjectively reported trust, mental workload, and situation awareness (henceforth "TWSA"). BACKGROUND: Subjective questionnaires are commonly used to assess human cognitive states. However, they are obtrusive and usually impractical to administer during operations. Measures derived from actions operators take while working (which we call "embedded measures") have been proposed as an unobtrusive way to obtain TWSA estimates. Embedded measures have not been systematically investigated for each of TWSA, which prevents their operational utility. METHODS: Fifteen participants completed twelve trials of spaceflight-relevant tasks while using a simulated autonomous system. Embedded measures of TWSA were obtained during each trial and participants completed TWSA questionnaires after each trial. Statistical models incorporating our embedded measures were fit with various formulations, interaction effects, and levels of personalization to understand their benefits and improve model accuracy. RESULTS: The stepwise algorithm for building statistical models usually included embedded measures, which frequently corresponded to an intuitive increase or decrease in reported TWSA. Embedded measures alone could not accurately capture an operator's cognitive state, but combining the measures with readily observable task information or information about participants' backgrounds enabled the models to achieve good descriptive fit and accurate prediction of TWSA. CONCLUSION: Statistical models leveraging embedded measures of TWSA can be used to accurately estimate responses on subjective questionnaires that measure TWSA. APPLICATION: Our systematic approach to investigating embedded measures and fitting models allows for cognitive state estimation without disrupting tasks when administering questionnaires would be impractical.

Individual and simultaneous treatment with antipsychotic aripiprazole and antidepressant trazodone inhibit sterol biosynthesis in the adult brain.

Polypharmacy, or the simultaneous use of multiple drugs to treat a single patient, is a common practice in psychiatry. Unfortunately, data on the health effects of commonly used combinations of medications are very limited. In this study, we therefore investigated the effects and interactions between two commonly prescribed psychotropic medications with sterol inhibiting side effects, trazodone (TRZ), an antidepressant, and aripiprazole (ARI), an antipsychotic. In vitro cell culture experiments revealed that both medications alone disrupted neuronal and astroglial sterol biosynthesis in dose-dependent manners. Furthermore, when ARI and TRZ were combined, exposure resulted in an additive 7-dehydrocholesterol (7-DHC) increase, as well as desmosterol (DES) and cholesterol decreases in both cell types. In adult mice, at baseline, we found that the three investigated sterols showed significant differences in distribution across the eight assessed brain regions. Furthermore, experimental mice treated with ARI or TRZ, or a combination of both medications for 8 days, showed strong sterol disruption across all brain regions. We show ARI or TRZ alone elevated 7-DHC and decreased DES levels in all brain regions, but with regional differences. However, the combined utilization of these two medications for 8 days did not lead to additive changes in sterol disturbances. Based on the complex roles of 7-DHC derived oxysterols, we conclude that individual and potentially simultaneous use of medications with sterol biosynthesis-inhibiting properties might have undesired side effects on the adult brain, with as yet unknown long-term consequences on mental or physical health.

Utility of the Full ECG Waveform for Stress Classification.

The detection of psychological stress using the electrocardiogram (ECG) signal is most commonly based on the detection of the R peak-the most prominent part of the ECG waveform-and the heart rate variability (HRV) measurements derived from it. For stress detection algorithms focused on short-duration time windows, there is potential benefit in including HRV features derived from the detection of smaller peaks within the ECG waveform: the P, Q, S, and T waves. However, the potential drawback of using these small peaks is their smaller magnitude and subsequent susceptibility to noise, making them more difficult to reliably detect. In this work, we demonstrate the potential benefits of including smaller waves within binary stress classification using a pre-existing data set of ECG recordings from 57 participants (aged 18-40) with a self-reported fear of spiders during exposure to videos of spiders. We also present an analysis of the performance of an automated peak detection algorithm and the reliability of detection for each of the smaller parts of the ECG waveform. We compared two models, one with only R peak features and one with small peak features. They were similar in precision, recall, F1, area under ROC curve (AUC), and accuracy, with the greatest differences less than the standard deviations of each metric. There was a significant difference in the Akaike Information Criterion (AIC), which represented the information loss of the model. The inclusion of novel small peak features made the model 4.29×1028 times more probable to minimize the information loss, and the small peak features showed higher regression coefficients than the R peak features, indicating a stronger relationship with acute psychological stress. This difference and further analysis of the novel features suggest that small peak intervals could be indicative of independent processes within the heart, reflecting a psychophysiological response to stress that has not yet been leveraged in stress detection algorithms.

Isolation and confinement due to the COVID-19 pandemic: Lessons for human spaceflight.

Background: Astronauts live and work in isolated, confined, extreme (ICE) environments that create both high stress and the need for high performance. The COVID-19 pandemic created ICE-like conditions across the globe by confining people to their homes under the ever-present threat of disease. Our goal is to understand the impact of prior experience in ICE on coping, using the pandemic as a pseudo space analog environment. Methods: We administered a survey three times with 7 days between administrations. A total of 82 participants completed all three survey sessions, and these participants were divided into three groups for analysis. The first group is those with prior experience in an ICE environment (n = 17; 7F/10 M), the second is those aged 30-55 with a master's or doctoral degree and without prior experience (n = 22; 10F/12 M), and the third is the general population (n = 43; 27F/16 M). Linear mixed models were used for statistical analysis of the results, given the unequal sample sizes. Results: The experienced group did not show healthier mental health scores than the astronaut-like group, but both groups displayed higher scores than the general population. However, work productivity scores for the experienced group were higher on average than the other two groups. Discussion: Results suggest that prior experience in ICE may improve the capability to maintain productivity-corresponding to the idea of resilience. However, experience may not improve mental health maintenance, suggesting that other approaches are needed to prepare astronauts for the mental health stressors of long-duration exploration missions.

Characterization of VU0468554, a New Selective Inhibitor of Cardiac G Protein-Gated Inwardly Rectifying K+ Channels.

G protein-gated inwardly rectifying K+ (GIRK) channels are critical mediators of excitability in the heart and brain. Enhanced GIRK-channel activity has been implicated in the pathogenesis of supraventricular arrhythmias, including atrial fibrillation. The lack of selective pharmacological tools has impeded efforts to investigate the therapeutic potential of cardiac GIRK-channel interventions in arrhythmias. Here, we characterize a recently identified GIRK-channel inhibitor, VU0468554. Using whole-cell electrophysiological approaches and primary cultures of sinoatrial nodal cells and hippocampal neurons, we show that VU0468554 more effectively inhibits the cardiac GIRK channel than the neuronal GIRK channel. Concentration-response experiments suggest that VU0468554 inhibits Gßγ-activated GIRK channels in noncompetitive and potentially uncompetitive fashion. In contrast, VU0468554 competitively inhibits GIRK-channel activation by ML297, a GIRK-channel activator containing the same chemical scaffold as VU0468554. In the isolated heart model, VU0468554 partially reversed carbachol-induced bradycardia in hearts from wild-type mice but not Girk4-/- mice. Collectively, these data suggest that VU0468554 represents a promising new pharmacological tool for targeting cardiac GIRK channels with therapeutic implications for relevant cardiac arrhythmias. SIGNIFICANCE STATEMENT: Although cardiac GIRK-channel inhibition shows promise for the treatment of supraventricular arrhythmias, the absence of subtype-selective channel inhibitors has hindered exploration into this therapeutic strategy. This study utilizes whole-cell patch-clamp electrophysiology to characterize the new GIRK-channel inhibitor VU0468554 in human embryonic kidney 293T cells and primary cultures. We report that VU0468554 exhibits a favorable pharmacodynamic profile for cardiac over neuronal GIRK channels and partially reverses GIRK-mediated bradycardia in the isolated mouse heart model.

Maternal cariprazine exposure inhibits embryonic and postnatal brain cholesterol biosynthesis.

Cariprazine (CAR) is a strong inhibitor of the Dhcr7 enzyme, the last enzyme in the cholesterol biosynthesis pathway. We assessed the effects of CAR on maternally exposed Dhcr7+/- and wild-type mouse offspring, and tested the biochemical effects of CAR in human serum samples. Dhcr7+/- and wild-type time-pregnant mice were exposed to vehicle or 0.2 mg/kg CAR from E12 to E19. Levels of CAR, CAR metabolites, sterols, and oxysterols were measured in the brain of maternally exposed offspring at various time points using LC-MS/MS. Embryonic exposure to CAR significantly increased levels of 7-DHC in all organs of exposed embryos, with a particularly strong effect in the brain. Detectable levels of CAR and elevated 7-DHC were observed in the brain of newborn pups 14 days after drug exposure. In addition, CAR altered sterol metabolism in all animals analyzed, with the strongest effect on the brain of Dhcr7+/- pups born to Dhcr7+/- dams. Furthermore, CAR elevated toxic oxysterols in the brain of maternally exposed Dhcr7+/- offspring to levels approaching those seen in a mouse model of Smith-Lemli-Opitz syndrome. Finally, we observed that patients taking CAR have elevated 7-DHC in their serum. In summary, maternal DHCR7 heterozygosity, combined with offspring DHCR7 heterozygosity might represent a vulnerability factor to medications that interfere with sterol biosynthesis. Due to the conserved sterol biosynthesis between mice and humans, we suggest that the 1-3% of patient population with single-allele DHCR7 mutations might not be ideal candidates for CAR use, especially if they are nursing, pregnant or plan to become pregnant.

Maternal aripiprazole exposure interacts with 7-dehydrocholesterol reductase mutations and alters embryonic neurodevelopment.

Mutations in both copies in the gene encoding 7-dehydrocholesterol reductase (DHCR7) cause Smith-Lemli-Opitz Syndrome (SLOS), which is characterized by a toxic elevation in 7-dehydrocholesterol (7-DHC). Aripiprazole (ARI) exposure, independent of genetic mutations, also leads to elevation of 7-DHC. We investigated the combined effect of a single-copy Dhcr7+/- mutation and maternal ARI exposure on the developing offspring brain. We generated a time-pregnant mouse model where WT and Dhcr7+/- embryos were maternally exposed to ARI or vehicle (VEH) from E12 to E19 (5 mg/kg). Levels of cholesterol, its precursors, ARI and its metabolites were measured at P0. We found that ARI and its metabolites were transported across the placenta and reached the brain of offspring. Maternal ARI exposure led to decreased viability of embryos and increased 7-DHC levels, regardless of maternal or offspring Dhcr7 genotype. In addition, Dhcr7+/- pups were more vulnerable to maternal ARI exposure than their WT littermates, and maternal Dhcr7+/- genotype also exacerbated offspring response to ARI treatment. Finally, both 7-DHC levels and 7-DHC/cholesterol ratio is the highest in Dhcr7+/- pups from Dhcr7+/- mothers exposed to ARI, underscoring a potentially dangerous interaction between maternal genotype×embryonic genotype×treatment. Our findings have important clinical implications. SLOS patients should avoid drugs that increase 7-DHC levels such as ARI, trazodone and haloperidol. In addition, treatment with 7-DHC elevating substances might be potentially unsafe for the 1-1.5% of population with single-allele disruptions of the DHCR7 gene. Finally, prenatal and parental genetic testing for DHCR7 should be considered before prescribing sterol-interfering medications during pregnancy.

Maximum Output and Low-Frequency Limitations of B71 and B81 Clinical Bone Vibrators: Implications for Vestibular Evoked Potentials.

OBJECTIVES: Bone-conducted vestibular evoked myogenic potentials (VEMPs) are tuned to have their maximum amplitude in response to tone bursts at or below 250 Hz. The low-frequency limitations of clinical bone vibrators have not been established for transient, tone burst stimuli at frequencies that are optimal for eliciting VEMPs. DESIGN: Tone bursts with frequencies of 250 to 2000 Hz were delivered to B71 and B81 bone vibrators and their output was examined using an artificial mastoid. The lower-frequency limit of the transducers was evaluated by examining the spectral output of the bone vibrators. Maximum output levels were evaluated by measuring input-output functions across a range of stimulus levels. RESULTS: Both the B71 and B81 could produce transient tone bursts with frequency as low as 400 Hz. However, tone bursts with frequencies of 250 and 315 Hz resulted in output with peak spectral energy at approximately 400 Hz. From 500 to 2000 Hz, maximum output levels within the linear range were between 120 and 128 dB peak force level. The newer B81 bone vibrator had a maximum output approximately 5 dB higher than the B71 at several frequencies. CONCLUSIONS: These findings demonstrate that both transducers can reach levels appropriate to elicit bone-conducted VEMPs, but the low-frequency limitations of these clinical bone vibrators limit tone burst frequency to approximately 400 Hz when attempting to stimulate the otolith organs via tone bursts.

Textile Electrocardiogram (ECG) Electrodes for Wearable Health Monitoring.

Wearable health-monitoring systems should be comfortable, non-stigmatizing, and able to achieve high data quality. Smart textiles with electronic elements integrated directly into fabrics offer a way to embed sensors into clothing seamlessly to serve these purposes. In this work, we demonstrate the feasibility of electrocardiogram (ECG) monitoring with sewn textile electrodes instead of traditional gel electrodes in a 3-lead, chest-mounted configuration. The textile electrodes are sewn with silver-coated thread in an overlapping zig zag pattern into an inextensible fabric. Sensor validation included ECG monitoring and comfort surveys with human subjects, stretch testing, and wash cycling. The electrodes were tested with the BIOPAC MP160 ECG data acquisition module. Sensors were placed on 8 subjects (5 males and 3 females) with double-sided tape. To detect differences in R peak detectability between traditional and sewn sensors, effect size was set at 10% of a sample mean for heart rate (HR) and R-R interval. Paired student's t-tests were run between adhesive and sewn electrode data for R-R interval and average HR, and a Wilcoxon signed-rank test was run for comfort. No statistically significant difference was found between the traditional and textile electrodes (R-R interval: t = 1.43, p > 0.1; HR: t = - 0.70, p > 0.5; comfort: V = 15,p > 0.5).

Improving access to appropriate post-exposure doxycycline for Lyme disease prophylaxis: role for community pharmacies.

The transmission of Borrelia burgdorferi to humans through tick bites results in Lyme disease. Appropriate therapy for Lyme disease is antibacterial drugs, most often doxycycline. Patients often approach community pharmacists for self-care assistance with the symptoms of Lyme disease: fever, headache, fatigue and skin rash. Pharmacists with the patient history are trained and capable of appropriately dispensing doxycycline to treat these patients and prevent the spread of infection to the joints, nerves or heart. We challenge restrictions to the appropriate and timely provision of therapy for Lyme disease and encourage the use of community pharmacists in managing these patients.

Microgravity-induced ocular changes are related to body weight.

On Earth, tissue weight generates compressive forces that press on body structures and act on the walls of vessels throughout the body. In microgravity, tissues no longer have weight, and tissue compressive forces are lost, suggesting that individuals who weigh more may show greater effects from microgravity exposure. One unique effect of long-duration microgravity exposure is spaceflight-associated neuroocular syndrome (SANS), which can present with globe flattening, choroidal folds, optic disk edema, and a hyperopic visual shift. To determine whether weight or other anthropometric measures are related to ocular changes in space, we analyzed data from 45 individual long-duration astronauts (mean age 47, 36 male, 9 female, mean mission duration 165 days) who had pre- and postflight measures of disk edema, choroidal folds, and manifest ocular refraction. The mean preflight weights of astronauts who developed new choroidal folds [78.6 kg with no new folds vs. 88.6 kg with new folds ( F = 6.2, P = 0.02)] and disk edema [79.1 kg with no edema vs. 95 kg with edema ( F = 9.6, P = 0.003)] were significantly greater than those who did not. Chest and waist circumferences were also significantly greater in those who developed folds or edema. The odds of developing disk edema or new choroidal folds were 55% in the highest- and 9% in the lowest-weight quartile. In this cohort, no women developed disk edema or choroidal folds, although women also weighed significantly less than men [62.9 vs. 85.2 kg ( F = 53.2, P < 0.0001)]. Preflight body weight and anthropometric factors may predict microgravity-induced ocular changes.

Dichlorophenyl piperazines, including a recently-approved atypical antipsychotic, are potent inhibitors of DHCR7, the last enzyme in cholesterol biosynthesis.

While antipsychotic medications provide important relief from debilitating psychotic symptoms, they also have significant adverse side effects, which might have relevant impact on human health. Several research studies, including ours, have shown that commonly used antipsychotics such as haloperidol and aripiprazole affect cholesterol biosynthesis at the conversion of 7-dehydrocholesterol (7-DHC) to cholesterol. This transformation is promoted by the enzyme DHCR7 and its inhibition causes increases in plasma and tissue levels of 7-DHC. The inhibition of this enzymatic step by mutations in the Dhcr7 gene leads to Smith-Lemli-Opitz syndrome, a devastating human condition that can be replicated in rats by small molecule inhibitors of DHCR7. The fact that two compounds, brexpiprazole and cariprazine, that were recently approved by the FDA have substructural elements in common with the DHCR7 inhibitor aripiprazole, prompted us to evaluate the effect of brexpiprazole and cariprazine on cholesterol biosynthesis. We report that cariprazine affects levels of 7-DHC and cholesterol in cell culture incubations at concentrations as low as 5 nM. Furthermore, a common metabolite of cariprazine and aripiprazole, 2,3-(dichlorophenyl) piperazine, inhibits DHCR7 activity at concentrations comparable to those of the potent teratogen AY9944. The cell culture experiments were corroborated in mice in studies showing that treatment with cariprazine elevated 7-DHC in brain and serum. The consequences of sterol inhibition by antipsychotics in the developing nervous system and the safety of their use during pregnancy remains to be established.

Separation anxiety among birth-assigned male children in a specialty gender identity service.

Previous research suggested that separation anxiety disorder (SAD) is overrepresented among birth-assigned male children clinic-referred for gender dysphoria (GD). The present study examined maternally reported separation anxiety of birth-assigned male children assessed in a specialty gender identity service (N = 360). SAD was determined in relation to DSM-III and DSM-IV criteria, respectively. A dimensional metric of separation anxiety was examined in relation to several additional factors: age, ethnicity, parental marital status and social class, IQ, gender nonconformity, behavioral and emotional problems, and poor peer relations. When defined in a liberal fashion, 55.8% were classified as having SAD. When using a more conservative criterion, 5.3% were classified as having SAD, which was significantly greater than the estimated general population prevalence for boys, but not for girls. Dimensionally, separation anxiety was associated with having parents who were not married or cohabitating as well as with elevations in gender nonconformity; however, the association with gender nonconformity was no longer significant when statistically controlling for internalizing problems. Thus, SAD appears to be common among birth-assigned males clinic-referred for GD when defined in a liberal fashion, and more common than in boys, but not girls, from the general population even when more stringent criteria were applied. Also, the degree of separation anxiety appears to be linked to generic risk factors (i.e., parental marital status, internalizing problems). As such, although separation anxiety is common among birth-assigned male children clinic-referred for GD, it seems unlikely to hold unique significance for this population based on the current data.

Pharmacy-Based Travel Health Services: State Approaches to Prescriptive Authority.

Pharmacists have provided travel health services in some capacity for more than 25 years. The ability of pharmacists to autonomously prescribe travel medications is growing. Three states (California, Idaho, and New Mexico) allow pharmacists to autonomously prescribe medications for international travel using the Centers for Disease Control and Prevention Yellow Book as a guide. Idaho also allows pharmacists to autonomously prescribe select medications appropriate to domestic travel (motion sickness prevention and Lyme disease prophylaxis), and Florida allows for the prescribing of drugs for motion sickness. Core elements from each state law including education, patient assessment, provider notification, and documentation are reviewed.

Fixed-Level Frequency Threshold Testing for Ototoxicity Monitoring.

OBJECTIVES: Hearing loss from ototoxicity is often most pronounced at high frequencies. To improve patient monitoring and compliance, high-frequency testing methods should be short and easy to administer. We evaluated the repeatability and accuracy of a Békésy-like, fixed-level frequency threshold (FLFT) technique. This test takes less than a minute and could provide a rapid and effective way to determine the highest audible frequency. We hypothesized the FLFT test would be repeatable in normal-hearing subjects, and accurate when compared with Békésy fixed-frequency audiometry in the sensitive region for ototoxicity (SRO). DESIGN: Twenty-nine normal-hearing subjects (20 females, 9 males) performed 2 different automated audiometry tests at least 4 times over a period of no less than 3 weeks. Ages ranged from 23 to 35 years (average = 28 years). Subjects completed testing under Sennheiser HDA-200 headsets. Initial fixed-frequency audiometry thresholds were obtained at frequencies ranging from 0.5 to 20 kHz to identify each subject's highest audible frequency, which was used to determine the SRO. The SRO was defined as the seven frequencies at and below the highest audible frequency in 1/6-octave steps. These frequencies were monitored with fixed-frequency audiometry. At each session, the FLFT test was administered at 80 dB SPL. Subjects used a Békésy-style tracking method to determine the frequency threshold. All testing was completed in a sound booth (single wall, Industrial Acoustics Company) using a computerized, laptop-based, system. FLFT repeatability was calculated as the root mean square difference from the first test session. FLFT accuracy was calculated as the difference from the highest audible frequency determined from fixed-frequency audiometry interpolated to 80 dB SPL level. RESULTS: The FLFT average RMSD for intersession variability was 0.05 ± 0.05 octaves. The test showed no learning effect [F(3,78) = 0.7; p = 0.6]. The overall intersession variability for SRO fixed-frequency audiometry thresholds at all frequencies was within clinically acceptable test-retest variability (10 dB) at 5.8 dB (range 2.7 to 9.9 dB). The SRO fixed-frequency audiometry therefore served as a repeatable basis of comparison for accuracy of the FLFT test. The mean absolute difference between the fixed-frequency audiometry and FLFT-determined highest audible frequency was 0.03 octaves. The FLFT and the highest audible frequency via fixed-frequency audiometry at 80 dB SPL were not different statistically (p = 0.12). The FLFT took approximately 30 seconds to complete, compared with approximately 4.5 min for fixed-frequency audiometry SRO and 20 to 25 min for a traditional ototoxic audiometric assessment. CONCLUSIONS: The Békésy-style FLFT was repeatable within 1/12 octave (1 step size in the testing procedure). The FLFT agreed well with the highest audible frequency determined via fixed-frequency audiometry at 80 dB SPL. The FLFT test is amenable to automatic and self-administration and may enable quick, accurate, noise-tolerant ototoxicity, and high-frequency hearing monitoring.

Mapping of Health Communication and Education Strategies Addressing the Public Health Dangers of Illicit Online Pharmacies.

Illicit online pharmacies are a growing global public health concern. Stakeholders have started to engage in health promotion activities to educate the public, yet their scope and impact has not been examined. We wished to identify health promotion activities focused on consumer awareness regarding the risks of illicit online pharmacies. Organizations engaged on the issue were first identified using a set of engagement criteria. We then reviewed these organizations for health promotion programs, educational components, public service announcements, and social media engagement. Our review identified 13 organizations across a wide spectrum of stakeholders. Of these organizations, 69.2% (n = 9) had at least one type of health promotion activity targeting consumers. Although the vast majority of these organizations were active on Facebook or Twitter, many did not have dedicated content regarding online pharmacies (Facebook: 45.5%, Twitter: 58.3%). An online survey administered to 6 respondents employed by organizations identified in this study found that all organizations had dedicated programs on the issue, but only half had media planning strategies in place to measure the effectiveness of their programs. Overall, our results indicate that though some organizations are actively engaged on the issue, communication and education initiatives have had questionable effectiveness in reaching the public. We note that only a few organizations offered comprehensive and dedicated content to raise awareness on the issue and were effective in social media communications. In response, more robust collaborative efforts between stakeholders are needed to educate and protect the consumer about this public health and patient safety danger.