Development of Gelled-Oil Nanoparticles for the Encapsulation and Release of Berberine.

In this study, a new drug carrier based on gelled-oil nanoparticles (GNPs) was designed and synthesized for the encapsulation and release of the model hydrophobic drug, berberine chloride (BCl). Two compositions with different oil phases were examined, sesame oil (SO) and cinnamaldehyde (Cin), which were emulsified with water, stabilized with Tween 80 (Tw80), and gelled using an N-alkylated primary oxalamide low-molecular-weight gelator (LMWG) to give stable dispersions of GNPs between 100 and 200 nm in size. The GNP formulation with Cin was significantly favored over SO due to (1) lower gel melting temperatures, (2) higher gel mechanical strength, and (3) significantly higher solubility, encapsulation efficiency, and loading of BCl. Also, the solubility and loading of BCl in Cin were significantly increased (at least 7-fold) with the addition of cinnamic acid. In vitro release studies showed that the release of BCl from the GNPs was independent of gelator concentration and lower than that for BCl solution and the corresponding nanoemulsion (no LWMG). Also, cell internalization studies suggested that the N-alkylated primary oxalamide LMWG did not interfere with the internalization efficiency of BCl into mouse mast cells. Altogether, this work demonstrates the potential use of these new GNP formulations for biomedical studies involving the encapsulation of drugs and nutraceuticals and their controlled release.

High-throughput identification of tuna (Thunnus spp.) larvae in the Gulf of Mexico using unlabelled-probe high-resolution melting analysis.

The genus Thunnus (family Scombridae) comprises eight species of tunas of which all but one are targeted by industrialized fisheries. Although intact individuals of these species can be distinguished by morphological characteristics, researchers and managers often rely on dressed, frozen, juvenile or larval fish samples, which often necessitates the identification of molecular species. Here the authors investigate short amplicon (SA) and unlabelled probe high-resolution melting analysis (UP-HRMA) as a low-cost, high-throughput molecular genotyping assay capable of distinguishing between albacore tuna (Thunnus alalunga), blackfin tuna (Thunnus atlanticus), bigeye tuna (Thunnus obesus), Atlantic bluefin tuna (Thunnus thynnus) and yellowfin tuna (Thunnus albacares) in the Gulf of Mexico. Although SA-HRMA of variable regions in the NADH dehydrogenase subunit 4 (ND4) and subunit 5 (ND5), and subunit 6 (ND6) of the mtDNA genome did yield some species-specific diagnostic melting curves (e.g., ND4 assay can reliably distinguish Atlantic bluefin tuna), genotype masking produced excessive variation in melting curves for reliable multi-species identification. To minimize the genotyping masking of SA-HRMA a 26 base pair long UP containing four SNPs was developed within a 133 bp segment of ND4. The UP-HRMA is able to reliably distinguish Gulf of Mexico species T. thynnus, T. obesus, T. albacares and T. atlanticus by UP melting temperature at 67, 62, 59 and 57°C, respectively. The developed UP-HRMA assay is a lower-cost, higher-throughput, alternative to previously published molecular assays for tuna identification that can be easily automated for large data sets, including ichthyological larval surveys, fisheries specimens lacking distinguishing morphological characteristics or detection of fraudulent trading of tuna species.

Evaluating Ultrasonicator Performance for Cyanobacteria Management at Freshwater Sources.

Algal blooms consisting of potentially toxic cyanobacteria are a growing source water management challenge faced by water utilities globally. Commercially available sonication devices are designed to mitigate this challenge by targeting cyanobacteria-specific cellular features and aim to inhibit cyanobacterial growth within water bodies. There is limited available literature evaluating this technology; therefore, a sonication trial was conducted in a drinking water reservoir within regional Victoria, Australia across an 18-month period using one device. The trial reservoir, referred to as Reservoir C, is the final reservoir in a local network of reservoirs managed by a regional water utility. Sonicator efficacy was evaluated through qualitative and quantitative analysis of algal and cyanobacterial trends within Reservoir C and surrounding reservoirs using field data collected across three years preceding the trial and during the 18-month duration of the trial. Qualitative assessment revealed a slight increase in eukaryotic algal growth within Reservoir C following device installation, which is likely due to local environmental factors such as rainfall-driven nutrient influx. Post-sonication quantities of cyanobacteria remained relatively consistent, which may indicate that the device was able to counteract favorable phytoplankton growth conditions. Qualitative assessments also revealed minimal prevalence variations of the dominant cyanobacterial species within the reservoir following trial initiation. Since the dominant species were potential toxin producers, there is no strong evidence that sonication altered Reservoir C's water risk profiles during this trial. Statistical analysis of samples collected within the reservoir and from the intake pipe to the associated treatment plant supported qualitative observations and revealed a significant elevation in eukaryotic algal cell counts during bloom and non-bloom periods post-installation. Corresponding cyanobacteria biovolumes and cell counts revealed that no significant changes occurred, excluding a significant decrease in bloom season cell counts measured within the treatment plant intake pipe and a significant increase in non-bloom season biovolumes and cell counts as measured within the reservoir. One technical disruption occurred during the trial; however, this had no notable impacts on cyanobacterial prevalence. Acknowledging the limitations of the experimental conditions, data and observations from this trial indicate there is no strong evidence that sonication significantly reduced cyanobacteria occurrence within Reservoir C.

The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130.

BACKGROUND: The protease BACE1 is a major drug target for Alzheimer's disease, but chronic BACE1 inhibition is associated with non-progressive cognitive worsening that may be caused by modulation of unknown physiological BACE1 substrates. METHODS: To identify in vivo-relevant BACE1 substrates, we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors. RESULTS: Besides SEZ6, the strongest, dose-dependent reduction was observed for the pro-inflammatory cytokine receptor gp130/IL6ST, which we establish as an in vivo BACE1 substrate. Gp130 was also reduced in human CSF from a clinical trial with a BACE inhibitor and in plasma of BACE1-deficient mice. Mechanistically, we demonstrate that BACE1 directly cleaves gp130, thereby attenuating membrane-bound gp130 and increasing soluble gp130 abundance and controlling gp130 function in neuronal IL-6 signaling and neuronal survival upon growth-factor withdrawal. CONCLUSION: BACE1 is a new modulator of gp130 function. The BACE1-cleaved, soluble gp130 may serve as a pharmacodynamic BACE1 activity marker to reduce the occurrence of side effects of chronic BACE1 inhibition in humans.

PBPK-PD modeling for the preclinical development and clinical translation of tau antibodies for Alzheimer's disease.

Disrupted tau proteostasis and transneuronal spread is a pathological hallmark of Alzheimer's disease. Neurodegenerative diseases remain an unmet medical need and novel disease modifying therapeutics are paramount. Our objective was to develop a mechanistic mathematical model to enhance our understanding of tau antibody pharmacokinetics and pharmacodynamics in animals and humans. A physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) modeling approach was employed to support the preclinical development and clinical translation of therapeutic antibodies targeting tau for the treatment of Alzheimer's disease. The pharmacokinetics of a tau antibody was evaluated in rat and non-human primate microdialysis studies. Model validation for humans was performed using publicly available clinical data for gosuranemab. In-silico analyses were performed to predict tau engagement in human brain for a range of tau antibody affinities and various dosing regimens. PBPK-PD modeling enabled a quantitative understanding for the relationship between dose, affinity, and target engagement, which supported lead candidate optimization and predictions of clinically efficacious dosing regimens.

Practical Strategies and Tools for Use by Occupational and Environmental Medicine Departments During COVID-19 Pandemic Surges.

OBJECTIVES: Occupational and environmental medicine (OEM) departments in healthcare institutions can be quickly overwhelmed when COVID-19 infection rates rapidly and simultaneously increase in the workforce and the patients served. Our goal is to present a detailed toolkit of practical approaches for use by front-line OEM specialists to address workforce management tasks during pandemic surges. METHODS: Specific focus is on tasks related to employee symptom triage, exposure risk assessment, workplace contact tracing, and work restrictions. RESULTS: Tools include strategies used by customer call centers, two decision support algorithms (exposure due to cohabitation or non-cohabitation), a color-coded employee case tracking tool, a contact tracing protocol, and documentation templates that serve as memory aids for encounters. CONCLUSIONS: These tools are created with commonly used software. Implementation is feasible in most front-line OEM settings, including those with limited resources.

Design and discovery of C2-fluoroalkyl iminothiazine dioxides as BACE inhibitors.

This paper describes the structure-activity-relationships of novel fluoroalkyl substituents at the C2 position of iminothiazine dioxide beta secretase inhibitors. Key discoveries include reduced amidine basicity and its effect on Pgp, cell potency, and efficacy in various preclinical in vivo efficacy animal models. Findings from these structure-activity-relationships are discussed.

Chronic Collection of Cerebrospinal Fluid from Rhesus Macaques (Macaca mulatta) with Cisterna Magna Ports: Update on Refinements.

More than 20 y ago, we developed an animal model for chronic and continuous collection of cerebrospinal fluid (CSF) from conscious rhesus macaques. Since our previous publication in 2003, we have successfully implanted 168 rhesus macaques using this approach. Our experience enables us to provide up-to-date information regarding the model, including refine- ments to our implant design, reductions in maintenance, and new procedures for dealing with contamination. The results of our experiences have reduced the number of surgeries required and helped to increase the longevity of the implant, with some functioning for more than 18 y. Building on our success in rhesus macaques, we attempted to develop similar animal models in the African green monkeys and dogs but have been unable to develop reliable chronic models for CSF collection in these species.

High-speed hyperspectral four-wave-mixing microscopy with frequency combs.

A four-wave-mixing, frequency-comb-based, hyperspectral imaging technique that is spectrally precise and potentially rapid, and can in principle be applied to any material, is demonstrated in a near-diffraction-limited microscopy application.

Special Forces Medical Sergeant/Special Operations Independent Duty Corpsman Candidates: Large Animal Module.

BACKGROUND: Medical care provided by Special Operations Forces (SOF) combat medics is vital for establishing communication with local populations. In many of these communities, livestock hold a valuable position within the social, political, and cultural structure. The West Virginia University (WVU) Special Forces Medical Sergeant/Special Operations Independent Duty Corpsman (SFMS/SOIDC) Large Animal Module is designed to provide a foundational experience in livestock husbandry and veterinary procedures to SOF combat medic candidates. This study was conducted to determine the participants' base knowledge of food animal production and to evaluate if the program content was sufficient for increasing their knowledge of the subject matter. METHODS: A quasi-experimental design utilizing pre-test and post-test instruments was used. The validity of the testing instruments was established by a panel of subject matter experts and the instruments' reliability was determined by a split-half analysis using SPSS® statistical software. The difference between the pre-test and post-test examinations were compared for 66 candidates who were assigned to WVU Health Sciences Center for the applied medical experience program and 46 counterparts assigned to other institutions by a match pair analysis. RESULTS: Seventy-five percent of the subjects had no previous livestock exposure, and only 7% had previously participated in the 4-H program or Future Farmers of America (FFA). The average improvement in scores, pre-test versus post-test, was significantly greater for those that attended the module (18.5 versus 0.9). CONCLUSION: Few SFMS/SOIDC candidates have prior knowledge of livestock husbandry practices. The large animal module successfully provides education on livestock husbandry practice to participants. Knowledge of livestock production can assist SOF medics in establishing rapport with indigenous populations while on mission.

A comparative network analysis of eating disorder psychopathology and co-occurring depression and anxiety symptoms before and after treatment.

BACKGROUND: Network analysis is an emerging approach in the study of psychopathology, yet few applications have been seen in eating disorders (EDs). Furthermore, little research exists regarding changes in network strength after interventions. Therefore the present study examined the network structures of ED and co-occurring depression and anxiety symptoms before and after treatment for EDs. METHOD: Participants from residential or partial hospital ED treatment programs (N = 446) completed assessments upon admission and discharge. Networks were estimated using regularized Graphical Gaussian Models using 38 items from the Eating Disorders Examination-Questionnaire, Quick Inventory of Depressive Symptomatology, and State-Trait Anxiety Inventory. RESULTS: ED symptoms with high centrality indices included a desire to lose weight, guilt about eating, shape overvaluation, and wanting an empty stomach, while restlessness, self-esteem, lack of energy, and feeling overwhelmed bridged ED to depression and anxiety symptoms. Comparisons between admission and discharge networks indicated the global network strength did not change significantly, though symptom severity decreased. Participants with denser networks at admission evidenced less change in ED symptomatology during treatment. CONCLUSIONS: Findings suggest that symptoms related to shape and weight concerns and guilt are central ED symptoms, while physical symptoms, self-esteem, and feeling overwhelmed are links that may underlie comorbidities in EDs. Results provided some support for the validity of network approaches, in that admission networks conveyed prognostic information. However, the lack of correspondence between symptom reduction and change in network strength indicates that future research is needed to examine network dynamics in the context of intervention and relapse prevention.

Identifying a male clinical cutoff on the Eating Disorder Examination-Questionnaire (EDE-Q).

OBJECTIVE: Evidence suggests that eating disorders (EDs) may be under-detected in males. Commonly used measures of EDs such as the Eating Disorder Examination-Questionnaire (EDE-Q) were initially developed within female samples, raising concern regarding the extent to which these instruments may be appropriate for detecting EDs in males. The current study used receiver operating characteristic curve analysis to (a) examine the accuracy of the EDE-Q global score in correctly classifying males with and without clinically significant ED pathology, and (b) establish the optimal EDE-Q global clinical cutoff for males. METHOD: Participants were a clinical sample of 245 male ED patients and a control sample of 205 male undergraduates. RESULTS: Eating Disorder Examination-Questionnaire global scores demonstrated moderate-high accuracy in predicting ED status (area under the curve = 0.85, 95% CI: 0.82-0.89). The optimal cutoff of 1.68 yielded a sensitivity of 0.77 and specificity of 0.77. DISCUSSION: Overall, results provide preliminary support for the discriminant validity of EDE-Q scores among males. However, concerns remain regarding the measure's ability to comprehensively assess domains of disordered eating most relevant to males. Therefore, careful attention to the possibility for measurement bias and continued evaluation of the scale in males is encouraged.

Optimum repetition rates for dual-comb spectroscopy.

The determination of the properties (i.e. line center, width, and amplitude) of a spectral line is simulated using a Monte Carlo method. For dual-comb spectroscopy, ideal repetition rates emerge for both the signal and LO combs that do not correspond to the repetition rates that possess the highest signal-to-noise ratio. The determination is even more accurate when the repetition rates have an arbitrary near-harmonic ratio. The simulation results are generalized to allow for the comparison of any two spectroscopic systems (i.e. not just comb-based systems) by performing the simulations as a function of the spectral point spacing and signal-to-noise ratio of the acquired data.

Affective predictors of the severity and change in eating psychopathology in residential eating disorder treatment: The role of social anxiety.

Despite evidence documenting relationships between eating disorder (ED) psychopathology, depression, and anxiety, little is known regarding how social anxiety is related to ED symptoms in treatment. Therefore this study examined associations between depression, general anxiety, social anxiety, and ED psychopathology at the beginning and end of treatment (EOT) among patients (N = 380) treated in a residential ED program. Participants completed measures of ED psychopathology and affective variables. Higher depression and general anxiety, but not social anxiety, were related to higher ED psychopathology at baseline. However, social anxiety emerged as a unique predictor of ED psychopathology at EOT such that participants with higher social anxiety evidenced less improvement in ED psychopathology. Findings suggest that social anxiety has specific relevance to treatment in EDs, which may reflect shared mechanisms and underlying deficits in emotion regulation.

Improvements in Resilience, Stress, and Somatic Symptoms Following Online Resilience Training: A Dose-Response Effect.

OBJECTIVE: To determine if participation in an online resilience program impacts resilience, stress, and somatic symptoms. METHODS: Approximately 600 enrollees in the meQuilibrium resilience program received a series of brief, individually prescribed video, and text training modules in a user-friendly format. Regression models tested how time in the program affected change in resilience from baseline and how changes in resilience affected change in stress and reported symptoms. RESULTS: A significant dose-response was detected, where increases in the time spent in training corresponded to greater improvements in resilience. Degree of change in resilience predicted the magnitude of reduction in stress and symptoms. Participants with the lowest resilience level at baseline experienced greater improvements. CONCLUSION: Interaction with the online resilience training program had a positive effect on resilience, stress, and symptoms in proportion to the time of use.

Male clinical norms and sex differences on the Eating Disorder Inventory (EDI) and Eating Disorder Examination Questionnaire (EDE-Q).

OBJECTIVE: Evidence indicates that males account for a significant minority of patients with eating disorders (EDs). However, prior research has been limited by inclusion of small and predominantly non-clinical samples of males. This study aimed to (1) provide male clinical norms for widely used ED measures (Eating Disorder Examination Questionnaire [EDE-Q] and Eating Disorder Inventory-3 [EDI-3]) and (2) examine sex differences in overall ED psychopathology. METHOD: Participants were 386 male and 1,487 female patients with an ED diagnosis aged 16 years and older who completed the EDE-Q and EDI-3 upon admission to a residential or partial hospital ED treatment program. RESULTS: Normative data were calculated for the EDE-Q (global and subscales) and the EDI-3 (drive for thinness, body dissatisfaction, and bulimia). Analyses of variance (ANOVAs) used to examine sex, ED diagnosis, and their interaction in relation to overall ED psychopathology revealed a consistent pattern of greater severity among females for ED psychopathology. DISCUSSION: This study provides clinical norms on the EDE-Q and the EDI-3 for males with clinically diagnosed EDs. It is unclear whether the greater severity observed in females reflects qualitative differences in ED presentation or true quantitative differences in ED severity. Additional research examining the underlying nature of these differences and utilizing male-specific ED measures with clinical samples is warranted.

The Effects of Hospital Safety Scores, Total Price, Out-of-Pocket Cost, and Household Income on Consumers' Self-reported Choice of Hospitals.

OBJECTIVES: The study measured the relative influence of the following 3 factors in consumers' choice of hospitals: (1) cost, (2) out-of-pocket cost, and (3) safety as measured by Leapfrog Hospital Safety Score letter grade. METHODS: Two hospital-choice questions regarding a hypothetical medical procedure were administered to 2357 online respondents. In question 1, respondents were assigned a scenario in which hospital 1 grade (A through D), hospital 2 grade (B through F), and hospital 2 total cost (3 levels) were randomly varied across respondents. In all cases, hospital 2 had a lower safety grade than hospital 1, and hospital 1 cost was held constant. In question 2, scenarios varied out-of-pocket cost rather than total cost. Demographic characteristics, income level, health status, health literacy, and opinions about value were also measured. RESULTS: On average, 94% and 88% of the respondents chose the safer hospital in questions 1 and 2, respectively. In all but 1 of 30 possible scenarios, where hospital 2 cost the individual $1000 less and was rated a B whereas hospital 1 was rated an A, respondents chose the safer hospital. Higher incomes, higher health literacy, and being female were associated with a stronger preference for hospital 1 (safer). There was a small effect suggesting that approximately 4% of the respondents selected a higher-cost hospital despite lower safety, but it was outweighed by predominant selections of the safer hospital. CONCLUSIONS: When shown Hospital Safety Score and cost information, consumers chose safer hospitals in 97% of cost and safety scenarios.