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In this paper we describe a microfabrication-derived approach for defining interactions between distinct groups of cells and integrating biosensors with cellular micropatterns. In this approach, photoresist lithography was employed to micropattern cell-adhesive ligand (collagen I) on silane-modified glass substrates. Poly(ethylene glycol) (PEG) photolithography was then used to fabricate hydrogel microstructures in registration with existing collagen I domains. A glass substrate modified in this manner had three types of micrpatterned regions: cell-adhesive collagen I domains, moderately adhesive silanized glass regions, and nonadhesive PEG hydrogel regions. Incubation of this substrate with primary rat hepatocytes or HepG2 cells resulted in attachment of hepatic cells on collagen I domains with no adhesion observed on silane-modified glass regions or hydrogel domains. 3T3 fibroblasts added onto the same surface attached on the glass regions around the hepatocytes, completing the coculture. Significantly, PEG hydrogel microstructures remained free of cells and were used to “fence” hepatocytes from fibroblasts, thus limiting communication between the cell types. We also demonstrated that entrapment of enzyme molecules inside hydrogel microstructures did not compromise nonfouling properties of PEG. Building on this result, horse radish peroxidase-containing hydrogel microstructures were integrated into micropatterned cocultures and were used to detect hydrogen peroxide in the culture medium. The surface micropatterning approach described here may be used in the future to simultaneously define and detect endocrine signaling between two distinct cell types. [ABSTRACT FROM AUTHOR]

Protein microarrays are rapidly emerging as valuable tools in creating combinatorial cell culture systems where inducers of cellular differentiation can be identified in a rapid and multiplexed fashion. In the present study, protein microarraying was combined with photoresist lithography to enable printing of extracellular matrix (ECM) protein arrays while precisely controlling “on-the-spot” cell−cell interactions. In this surface engineering approach, the micropatterned photoresist layer formed on a glass substrate served as a temporary stencil during the microarray printing, defining the micrometer-scale dimensions and the geometry of the cell-adhesion domains within the printed protein spots. After removal of the photoresist, the glass substrates contained micrometer-scale cell-adhesive regions that were encoded within 300 or 500 m diameter protein domains. Fluorescence microscopy and atomic force microscopy (AFM) were employed to characterize protein micropatterns. When incubated with micropatterned surfaces, hepatic (HepG2) cells attached on 300 or 500 m diameter protein spots; however, the extent of cell−cell contacts within each spot varied in accordance with dimensions of the photoresist stencil, from single cells attaching on 30 m diameter features to multicell clusters residing on 100 or 200 m diameter regions. Importantly, the photoresist removal process was shown to have no detrimental effects on the ability of several ECM proteins (collagens I, II, and IV and laminin) to support functional hepatic cultures. The micropatterning approach described here allows for a small cell population seeded onto a single cell culture substrate to be exposed to multiple scenarios of cell−cell and cell−surface interactions in parallel. This technology will be particularly useful for high-throughput screening of biological stimuli required for tissue specification of stem cells or for maintenance of differentiated phenotype in scarce primary cells. [ABSTRACT FROM AUTHOR]

Objective: To assess whether preferential hiring practices, particularly self-hiring, are present in academic otolaryngology departments. Setting: A list of academic Otolaryngology-Head and Neck Surgery (O-HNS) departments ranked #1-40 was generated from the Doximity 2021 rankings. The educational background and training information of clinical faculty members and departmental leadership was extracted from each department's online directories. Methods: Descriptive statistics were used to examine inter/intradepartmental relationships and affiliations of included clinical faculty and departmental leadership based on current employment and medical training sites. A "prior affiliation ratio" was calculated to assess the degree of self-hiring and account for multiple possible prior affiliations (medical school, residency, and fellowship) by dividing all prior self-hired affiliations of faculty by the total number of faculty at each department. Results: A total of 1344 clinical faculty were identified, and 596 (44.35%) had at least 1 prior affiliation with their department. The overall prior affiliation ratio was 0.6, and 7 departments had a value >0.8, with the highest being 1.27 (>1.0 indicating multiple prior affiliations per individual such as both residency and fellowship). A network map of departments #1-10 showed heavy intradepartmental faculty recruitment with 24% of faculty having completed a #1-10 residency, 24% a #11-20 residency, 13% a #21-30 residency, and 11% a #31-40 residency. Totaling this data, 76% of faculty at departments ranked #1-10 had completed training at a program ranked #1-40. Furthermore, our data shows high rates of self-hiring among departmental leadership, (40% of Departmental Chairs and 62.5% of Program Directors) though rates are not significantly higher than self-hiring among faculty overall. Conclusion: The top 40 ranked O-HNS departments have high rates of self-hiring, relying on prestige of training programs and prior affiliation in hiring decisions. The effect on departmental productivity and training is unclear., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Robert F. Labadie is a consultant for Spiral Therapeutics and receives NIH funding for other projects.

Importance: Meniere disease accounts for up to 15% of new vestibular diagnoses,; however, the optimal treatment has yet to be identified. A conservative treatment that would reduce or stop the vertigo episodes has not been identified., Objective: To determine the efficacy of a serotonin-norepinephrine reuptake inhibitor, venlafaxine, compared to placebo in treating patients with Meniere disease., Design, Setting, and Participants: This was a randomized, double-blind, placebo-controlled, crossover pilot study spanning 22 weeks of follow-up. The clinical trial took place at a single-center tertiary referral center in Charleston, South Carolina. Participants were eligible if they were 18 years or older, had definite Meniere disease criteria as defined by Barany criteria, had at least 2 episodes in the last month, had not received intratympanic gentamycin, skull base surgery, or radiation therapy to the head or neck, not currently taking diuretics for Meniere disease, not currently taking oral steroids, and not currently taking serotonin-modulating medication. Patients were enrolled between February 2020 and September 2023., Interventions: Patients received either 1 venlafaxine tablet, 37.5 mg, taken daily by mouth for 8 weeks or 1 placebo tablet taken daily by mouth for 8 weeks. Group 1 received placebo during phase 1 of the trial and venlafaxine in phase 2 of the trial. Group 2 received venlafaxine during phase 1 of the trial and placebo in phase 2 of the trial., Main Outcomes and Measures: The main outcomes included the number of episodes and scores on the following scales: Dizziness Handicap Inventory, Neuropsychological Vertigo Inventory, Meniere Disease Patient-Oriented Symptom Index, 20-Item Short Form Health Survey, Penn State Worry Questionnaire, Cognitive Failure Questionnaire., Results: A total of 182 patients were screened, and 40 participants with Meniere disease enrolled in the trial. The mean (SD) age of participants was 56.6 (14.3) years, and 22 (55%) were female. Participants had a mean (SD) of 13.8 (10.1) episodes per phase at baseline, 5.4 (4.4) episodes (Δ8.4) during the venlafaxine phase, and 5.0 (4.6) episodes (Δ8.8) during the placebo phase. No significant difference was identified between venlafaxine and placebo groups in the number of episodes or quality-of-life metrics., Conclusions and Relevance: This randomized clinical trial failed to identify a difference between venlafaxine and placebo in number of episodes and other quality-of-life metrics. Future studies may benefit from different dosing regimens, larger cohorts, and longer lengths of therapy., Trial Registration: ClinicalTrials.gov Identifier: NCT04218123.

Objective: High Performance liquid chromatography is an integral analytical tool in assessing drug product stability. A simple, selective, precise, accurate and stability indicating RP-HPLC method was developed and validated for analysis of Tadalafil and Macitentan in synthetic mixture., Material and Method: Chromatographic separation was performed using Phenomex Gemini C18 (25cm×4.6nm, 5μm) Column. The mobile phase consists of (10mM Ammonium Acetate in water and [Methanol: ACN 20: 80% v/v]) (40: 60% v/v). The flow rate was set to be 1.0mL/min. The injection volume was 10.00μL. The detection was carried out at 260nm at column temperature 35°C., Results: The method was validating according to ICH Q 2 R 1 guideline for accuracy, precision, reproducibility, specificity, robustness and detection and quantification limits. Stability testing was performed on Tadalafil and Macitentan and it was found that these degraded sufficiently in all applied chemical and physical conditions. Linearity for Tadalafil and Macitentan was observed 0.4-100μg/mL and 0.1-25μg/mL with correlation coefficient at 0.9999. LOD and LOQ 0.008μg/mL and 0.024μg/mL and 0.001μg/mL and 0.0029μg/mL for Tadalafil and Macitentan respectively., Conclusion: The developed RP-HPLC method was found to be suitable for the determination of both the drugs., (Copyright © 2023 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Phytopharmaceuticals, derived from natural sources, manifest tremendous potential for therapeutic applications. Nevertheless, effective delivery of these bio-actives presents significant challenges. A breakthrough in fortifying phytopharmaceuticals within phosphatidylcholine is a promising remedy to overcome solubility, permeability, and other related drawbacks. This intrinsic lipid, which is obtained from both natural and synthetic sources, confers numerous benefits, encompassing heightened solubility, augmented bioavailability, and enhanced stability. The conjugation of phytopharmaceuticals with phosphatidylcholine enables improved dermal permeation, absorption, targeted distribution, and the possibility of synergistic results, eventually improving therapeutic efficacy. Additionally, the use of phytopharmaceuticals enriched with phosphatidylcholine presents a promising route for overcoming the limitations imposed by conventional delivery techniques, encouraging more effective treatments. The review provides a thorough analysis of phosphatidylcholine- incorporated phytopharmaceuticals as nanomedicine with variables that significantly affect their therapeutic efficacy. Moreover, the review elaborates on how phosphatidylcholine improves solubility, permeability, and tissue distribution and boosts the potential of phytopharmaceuticals. Further, the review underscores the significance of nano-formulation strategies, analytical methodologies, and forthcoming prospects to propel this field forward. Furthermore, the review emphasizes the potential inherent in this innovative approach while highlighting the importance of additional research endeavors and collaborative initiatives to unlock the therapeutic benefits of phosphatidylcholinefortified phytopharmaceuticals, enhancing patient well-being., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: Evaluate the measurement properties of the Dizziness Handicap Inventory (DHI) using item response theory in patients diagnosed with vestibular migraine (VM) and Meniere's disease (MD)., Design: One hundred twenty-five patients diagnosed with VM and 169 patients diagnosed with MD by a vestibular neurotologist according to the Bárány Society criteria in two tertiary multidisciplinary vestibular clinics and who completed the DHI at their initial visit, were included in the study. The DHI (total score and individual items) was analyzed using the Rasch Rating Scale model for patients in each subgroup, VM and MD, and as a whole group. The following categories were assessed: rating-scale structure, unidimensionality, item and person fit, item difficulty hierarchy, person-item match, and separation index, standard error of measurement, and minimal detectable change (MDC)., Results: Patients were predominantly female (80% of the VM subgroup and 68% of the MD subgroup) with a mean age of 49.9 ± 16.5 years and 54.1 ± 14.2 years, respectively. The mean total DHI score for the VM group was 51.9 ± 22.3 and for the MD group was 48.5 ± 26.6 ( p > 0.05). While neither all items nor the separate constructs met all criteria for unidimensionality (i.e., items measuring a single construct), post hoc analysis showed that the all-item analysis supported a single construct. All analyses met the criterion for showing a sound rating scale and acceptable Cronbach's alpha (≥0.69). The all-item analysis showed the most precision, separating the samples into three to four significant strata. The separate-construct analyses (physical, emotional, and functional) showed the least precision, separated the samples into less than three significant strata. Regarding MDC, the MDC remained consistent across the analyses of the different samples; approximately 18 points for the full analyses and approximately 10 points for the separate construct (physical, emotional, and functional)., Conclusions: Our evaluation of the DHI using item response theory shows that the instrument is psychometrically sound and reliable. The all-item instrument fulfills criteria for essential unidimensionality but does seem to measure multiple latent constructs in patients with VM and MD, which has been reported in other balance and mobility instruments. The current subscales did not show acceptable psychometrics, which is in line with multiple recent studies favoring the use of the total score. The study also shows that the DHI is adaptable to episodic recurrent vestibulopathies. The total score shows better precision and separation of subjects in up to four strata compared to the separate construct that separate subjects into less than three strata. The measurement error smallest detectable change was found in our analysis to be 18 points, which means any change in the DHI of less than 18 points is not likely to be clinically significant. The minimal clinically important difference remains indeterminate., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To perform a systematic review of otolaryngologic presentation rates to emergency department settings before and after lockdown due to the COVID-19 pandemic., Sources: PubMed, Scopus, and CINAHL., Methods: A systematic search was conducted following PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-analyses) for studies describing otolaryngologic presentations to emergency department and rapid access clinic settings both in the before-lockdown and after-lockdown periods. The start of after-lockdown period varied based on initiation of lockdown, ranging from March 1st to June 1st of 2020 across general emergency department studies., Results: A total of 14 studies were included in this review. About 10 were general emergency departments, 3 were specifically pediatric emergency departments, and 1 study focused on the geriatric population (>65 years). A total of 13 790 patients were included, with 9446 in the before-lockdown period (68.5%) and 4344 in the after-lockdown period (31.5%). Meta-analysis of proportions for otolaryngologic presentations across general emergency departments was performed. Comparison of weighted proportions found significant differences between before-lockdown and after-lockdown presentation rates for infectious etiologies, tonsillitis specifically, foreign bodies, non-infectious airway issues, and epistaxis among these studies., Conclusions: The increased proportions of various non-infectious presentations (eg, epistaxis, foreign bodies, and airway issues) following lockdown might be associated with proportional decreases in infectious pathologies, given decreased social contact to prevent SARS-CoV-2 transmission. Overall, it is important for otolaryngologists to recognize what presentations might more commonly be seen and require evaluation and potential intervention in light of a global pandemic.

Secondary autoimmune inner ear disease (AIED) is often bilateral and asymmetric in patients presenting with audiovestibular symptoms due to a systemic autoimmune disease. This systematic review and meta-analysis are aimed at identifying and highlighting patterns in prevalence of vestibular dysfunction, symptom presentation, and diagnostic methods in extant literature by combining clinical context from case reports with quantitative analyses from cohort studies. Screening of articles by title, abstract, and full text was completed by four reviewers (K.Z., A.L., S.C., and S.J.). In this study, we grouped secondary AIED and systemic autoimmune diseases by pathophysiologic mechanism: (1) connective tissue disease (CTD), (2) vasculitides (VAS), (3) systemic inflammatory disorders (SID), and (4) other immune-mediated disorders (OIMD). The search for AIED disease identified 120 articles (cohorts and case reports) that met the final inclusion criteria. All 120 were included in the qualitative review, and 54 articles were included for meta-analysis. Of these 54 articles, 22 included a control group (CwC). Ninety individual cases or patient presentations from 66 articles were included for analysis in addition to the 54 cohort articles. Secondary AIED does not have a diagnostic algorithm for managing vestibular symptoms. The management of audiovestibular symptoms requires close collaboration between otolaryngologists and rheumatologists to preserve end-organ function of the ear. To improve our ability to understand the impact on the vestibular system, vestibular clinicians need to develop a standardized reporting method. Clinical presentation should frequently be paired with vestibular testing to contextually investigate symptom severity and provide higher quality care., (© 2023. International League of Associations for Rheumatology (ILAR).)

Background: Implant-based breast augmentation is one of the most popular plastic surgery procedures performed worldwide. As the number of patients who have breast implants continues to rise, so does the number of those who request breast implant removal without replacement. There is little in the current scientific literature describing total intact capsulectomy and simultaneous mastopexy procedures., Objectives: Here, the authors present their current method using the mammary imbrication lift and fixation technique after explant and total capsulectomy., Methods: Between 2016 and 2021, a total of 64 patients (mean age: 42.95 years; range, 27-78 years) underwent the described mammary imbrication lift and fixation technique with bilateral breast implant removal and total capsulectomy., Results: Mean follow-up was 6.5 months (range, 1-36 months). Postoperative complications included minor cellulitis in 1 patient (1.6%), late onset hematoma with infection in 1 patient (1.6%), fat necrosis and pulmonary embolism in 1 patient with prior history of thromboembolic events (1.6%), and breast scar irregularity in 4 patients (6.2%) who required subsequent minor scar revision or steroid injections. Two patients (1.6%) underwent revision surgery with bilateral breast fat grafting to improve shape and add volume., Conclusions: The mammary imbrication lift and fixation technique described here can safely and simultaneously be performed with a total intact capsulectomy and explant procedure. This technique avoids wide undermining, intentionally opening the capsule, performing subtotal capsulectomy, and preserving blood supply to the breast tissue and nipple with low complication rates., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Aesthetic Society.)

Objectives: To evaluate the outcomes of cochlear implantation in patients with severe to profound sensorineural hearing loss due to inner ear malformations (IEMs) when compared to patients without IEMs. We discussed audiological outcomes such as open-set testing, closed-set testing, CAP score, and SIR score as well as postoperative outcomes such as cerebrospinal fluid gusher and incomplete insertion rate associated with cochlear implantation in individuals with IEMs., Data Sources: PubMed, Science Direct, Web of Science, Scopus, and EMBASE databases., Review Methods: After screening a total of 222 studies, twelve eligible original articles were included in the review to analyze the speech and hearing outcomes of implanted patients with IEMs. Five reviewers independently screened, selected, and extracted data. The "Tool to Assess Risk of Bias in Cohort Studies" published by the CLARITY group was used to perform quality assessment on eligible studies. Systematic review registration number: CRD42021237489., Results: IEMs are more likely to be associated with abnormal position of the facial nerve, raising the risk of intraoperative complications. These patients may benefit from cochlear implantation, but audiological outcomes may also be less favorable than in individuals without IEMs. Furthermore, due to the risk of cerebrospinal fluid gusher, incomplete insertion of electrodes, and postoperative facial nerve stimulation, surgeons can employ precautionary measures such as preoperative imaging and proper counseling. Postoperative imaging is suggested to be beneficial in ensuring proper electrode placement., Conclusions: Cochlear implants (CIs) have the potential to provide auditory rehabilitation to individuals with IEMs. Precise classification of the malformation, preoperative imaging and anatomical mapping, appropriate electrode selection, intra-operative techniques, and postoperative imaging are recommended in this population., Competing Interests: The authors have declared that no competing interests exist.

DPP-4 inhibitors have been shown to reverse amyloid deposition in Alzheimer's disease (AD) patients with cognitive impairment. Ocimum sanctum L. leaves reported the presence of important phytoconstituents which are reported to have DPP-4 inhibitory activity. To investigate the effects of petroleum ether extract of Ocimum sanctum L. (PEOS) in Intracerebroventricular streptozotocin (ICV-STZ) induced AD rats. ICV-STZ (3 mg/kg) was injected bilaterally into male Wistar rats, while sham animals received the artificial CSF. The ICV-STZ-induced rats were administered with three doses of PEOS (100, 200, and 400 mg/kg, p.o.) for thirty days. All experimental rats were subjected to behaviour parameters (radial arm maze task and novel object recognition test), neurochemical parameters such as GLP-1, Aβ42, and TNF-α levels, and histopathological examination (Congo red staining) of the left brain hemisphere. PEOS significantly reversed the spatial learning and memory deficit exhibited by ICV-STZ-induced rats. Furthermore, PEOS also shows promising results in retreating Aβ deposition, TNF α, and increasing GLP-1 levels. The histopathological study also showed a significant dose-dependent reduction in amyloid plaque formation and dense granule in PEOS -treated rats as compared to the ICV-STZ induced rats (Negative control). The results show that extract of Ocimum sanctum L. attenuated ICV-STZ-induced learning and memory deficits in rats and has the potential to be employed in the therapy of AD., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Lipid-based emulsion system - a subcategory of emulsion technology, has emerged as an enticing option to improve the solubility of the steadily rising water-insoluble candidates. Along with enhancing solubility, additional advantages such as improvement in permeability, protection against pre-systemic metabolism, ease of manufacturing, and easy to scale-up have made lipid-based emulsion technology very popular among academicians and manufacturers. The present article provides a comprehensive review regarding various critical properties of lipid-based emulsion systems, such as microemulsion, nanoemulsion, SMEDDS (self microemulsifying drug delivery system), and SNEDDS (self nanoemulsifying drug delivery system). The present article also explains in detail the similarities and differences between them, the stabilization mechanism, methods of preparation, excipients used to prepare them, and evaluation techniques. Subtle differences between nearly related terminologies such as microemulsion and nanoemulsion, SMEDDS, and SNEDDS are also explained in detail to clarify the basic differences. The present article also gives in-depth information regarding the chemical structure of various lipidic excipients, various possible chemical modifications to modify their inherent properties, and their regulatory status for rational selection., (© 2021. Controlled Release Society.)

Purpose: Postoperative radiation therapy (RT) is commonly used for World Health Organization grade II-III intracranial ependymoma. Clinicians generally aim to begin RT ≤5 weeks after surgery, but postoperative recovery and need for second look surgery can delay the initiation of adjuvant therapy. On ACNS 0831, patients were required to enroll ≤8 weeks after initial surgery and begin adjuvant therapy within 3 weeks after enrollment. The purpose of this study was to determine the optimal timing of RT after surgery., Methods and Materials: The National Cancer Database was queried for patients (aged 1-39 years) with localized World Health Organization grade II-III intracranial ependymoma treated with surgery and postoperative RT. Overall survival (OS) curves were plotted based on RT timing (≤5 weeks, 5-8 weeks, and >8 weeks after surgery) and were compared by log-rank test. Factors associated with OS were identified by multivariate analysis. After 2009, complete data were available on whether patients underwent gross total resection or subtotal resection. Planned subset analysis was performed to examine the effect of RT timing on OS in patients with known extent of resection., Results: In the final analytical data set of 1043 patients, no difference in 3-year OS was observed in patients who initiated RT ≤5 weeks, 5 to 8 weeks, and >8 weeks after surgery (89.8% vs 89.1% vs 88.4%; P  = .796). On multivariate analysis, grade III tumors (hazard ratio, 2.752; 95% confidence interval, 1.969-3.846, P < .001) and subtotal resection (hazard ratio, 2.253; 95% confidence interval, 1.405-3.611, P < .001) were significantly associated with reduced OS. Timing of RT, total RT dose, age, and other factors were not significant. These findings were affirmed in the subset of patients treated between 2010 and 2016, when extent of resection was routinely recorded., Conclusions: Delayed postoperative RT was not associated with inferior survival in patients with intracranial ependymoma. Delayed RT initiation may be acceptable in patients who require longer postoperative recovery or referral to an appropriate RT center, but should be minimized whenever practical., (© 2021 The Author(s).)

Background: Levofloxacin has been recommended by the WHO for the treatment of pulmonary tuberculosis and inhalable delivery of levofloxacin can be advantageous over conventional delivery., Objective: This study aimed to develop and optimize inhalable levofloxacin Loaded Chitosan Nanoparticles (LCN). The objective was to achieve the mean particle size of LCN less than 300nm, sustain the drug release up to 24 h, and achieve MMAD of LCN of less than 5μm., Methods: LCN were prepared by ionic gelation of chitosan with sodium tripolyphosphate (STPP) and subsequent lyophilization. A Plackett Burman screening design, 32 full factorial design, and overlay plots were sequentially employed to optimize the formulation. The mean particle size, % entrapment efficiency, in vitro drug release, and minimum inhibitory concentration were all evaluated., Results: The Pareto chart from the Placket Burman screening design revealed that the concentrations of chitosan and STPP was found to be significant (p < 0.05). Further analysis by 32 full factorial design revealed that F-ratio for each model generated was found to be greater than the theoretical value (p < 0.05), confirming the significance of each model., Conclusion: The optimized formulation showed a mean particle size of 171.5 nm, sustained the drug release up to 24 h in simulated lung fluid, and revealed MMAD of 3.18 μm, which can confirm delivery of the drug to the deep lung region. However, further in vivo studies are required to design a suitable dosage regimen and establish the fate of nanoparticles for safe and efficacious delivery of the drug., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Dual-energy CT (DECT) can improve the accuracy of myocardial perfusion CT with projection-based monochromatic (DECT-MCE) and quantification of myocardial iodine in material decomposition (DECT-MD) reconstructions. However, evaluation of multiple reconstructions is laborious and the optimal reconstruction to detect myocardial perfusion defects is unknown., Methods: Left ventricular (LV) phantoms with artificial perfusion defects were scanned using DECT and single energy cardiac computed tomography angiography (SECT). Reconstructions of DECT-MCE at 40, 70, 100 and 140 keV, DECT-MD pairs of water, iodine, iron and fat, and SECT were evaluated using a 17-segment myocardial model. The diagnostic performance of each reconstruction was calculated on a per-segment basis and compared across DECT reconstructions., Results: Over 34 phantoms with artificial perfusion defects were found in 64/578 (11%) of segments, the sensitivity of DECT-MCE at 40, 70, 100, and 140 keV was 100% (95% confidence interval (CI): 93-100), 100% (95% CI: 93-100), 71% (95% CI: 56-83), and 25% (95% CI: 14-40), respectively, with a significant decline between 70 keV and 100 keV (p < 0.001). The specificity of DECT-MCE was 100% at all energies (95% CI: 99-100). As a group, the DECT-MD iodine background reconstructions had significantly lower sensitivity than the remaining modes (2.1% [95% CI, 0.05-11.1], vs. 100% [95% CI, 92.6-100], p < 0.001). Specificity of all material pair modes remained 100%., Conclusions: Using LV phantom models, the approach with the best sensitivity and specificity to assess myocardial perfusion defects with DECT are reconstructions of DECT-MCE at 40 or 70 KeV and DECT-MD without iodine background., Competing Interests: Conflict of interest Dr. James K. Min receives funding from GE Healthcare and serves on the scientific advisory board of Arineta and GE Healthcare. Dr. Min also has an equity interest in and is an employee of Cleerly, Inc. The remaining authors have no relevant disclosures, (Copyright © 2019. Published by Elsevier Inc.)

The present investigation was carried out to design, optimize, and evaluate lurasidone hydrochloride nanocrystals for improving its solubility and dissolution characteristics. Nanocrystals were prepared by media milling technique using zirconium oxide beads with 0.1 mm diameter. Various stabilizers, viz. poloxamer 188, PVP K30, SLS, HPMC E15, and PVP S 630 D, were evaluated to stabilize the nanocrystals. The Pareto chart obtained through Plackett-Burman screening design revealed that HPMC E 15 showed the highest standardized effect (p value <0.05) on percent dissolution efficiency at 2 min. In subsequent studies, a 3(2) factorial design was employed to quantify the effect of two independent variables, namely amount of stabilizer and milling time on predetermined response variables mean particle size, saturation solubility, and percent dissolution efficiency at 2 min. Statistical analysis of the factorial design revealed that all predetermined response variables were significantly dependent (p value <0.05) on the independent variables. The observed response of the optimized batch prepared as per the desirability function was in close agreement with predicted response, and mathematical model generated was validated. The optimized batch was lyophilized, and X-ray powder diffraction studies indicated that there was no substantial change in crystallinity of the drug. The optimized formulation showed mean particle size of 228 nm and released almost all the drug within first 5 min. Since the crystallinity of the drug is maintained, improvement in saturation solubility and dissolution efficiency could be attributed to decrease in mean particle size of the drug.

Patients with non-valvular atrial fibrillation (AF) have an elevated stroke risk that is 2-7 times greater than in those without AF. Intravenous unfractionated heparin (UFH) is commonly used for hospitalized patients with atrial fibrillation and atrial flutter (AFL) to prevent stroke. Dosing strategies exist for intravenous anticoagulation in patients with acute coronary syndromes and venous thromboembolic diseases, but there are no data to guide providers on a dosing strategy for intravenous anticoagulation in patients with AF/AFL. 996 hospitalized patients with AF/AFL on UFH were evaluated. Bolus dosing and initial infusion rates of UFH were recorded along with rates of stroke, thromboemobolic events, and bleeding events as defined by the International Society on Thrombosis and Haemostasis criteria. Among 226 patients included in the analysis, 76 bleeding events occurred. Using linear regression analysis, initial rates of heparin infusion ranging from 9.7 to 11.8 units/kilogram/hour (U/kg/h) resulted in activated partial thromboplastin times that were within therapeutic range. The median initial infusion rate in patients with bleeding was 13.3 U/kg/h, while in those without bleeding it was 11.4 U/kg/h; p = 0.012. An initial infusion rate >11.0 U/kg/h yielded an OR 1.95 (1.06-3.59); p = 0.03 for any bleeding event. Using IV heparin boluses neither increased the probability of attaining a therapeutic aPTT (56.1 vs 56.3 %; p = 0.99) nor did it significantly increase bleeding events in the study (35.7 vs 31.3 %; p = 0.48). The results suggest that higher initial rates of heparin are associated with increased bleeding risk. From this dataset, initial heparin infusion rates of 9.7-11.0 U/kg/h without a bolus can result in therapeutic levels of anticoagulation in hospitalized patients with AF/AFL without increasing the risk of bleeding.

Even when treated with aggressive current therapies, most patients with glioblastoma survive less than two years. Rapid tumor growth, an invasive nature, and the blood-brain barrier, which limits the penetration of large molecules into the brain, all contribute to the poor tumor response associated with conventional therapies. Immunotherapy has emerged as a therapeutic approach that may overcome these challenges. We recently reported that single-walled carbon nanotubes (SWCNTs) can be used to dramatically increase the immunotherapeutic efficacy of CpG oligonucleotides in a mouse model of glioma. Following implantation in the mouse brain, the tumor cell line used in these previous studies (GL261) tends to form a spherical tumor with limited invasion into healthy brain. In order to evaluate SWCNT/CpG therapy under more clinically-relevant conditions, here we report the treatment of a more invasive mouse glioma model (K-Luc) that better recapitulates human disease. In addition, a CpG sequence previously tested in humans was used to formulate the SWCNT/CpG which was combined with temozolomide, the standard of care chemotherapy for glioblastoma patients. We found that, following two intracranial administrations, SWCNT/CpG is well-tolerated and improves the survival of mice bearing invasive gliomas. Interestingly, the efficacy of SWCNT/CpG was enhanced when combined with temozolomide. This enhanced anti-tumor efficacy was correlated to an increase of tumor-specific cytotoxic activity in splenocytes. These results reinforce the emerging understanding that immunotherapy can be enhanced by combining it with chemotherapy and support the continued development of SWCNT/CpG.

We present an integrated and low-cost microfluidic platform capable of extraction of nucleic acids from real biological samples. We demonstrate the application of this platform in pathogen detection and cancer screening. The integrated platform consists of three units including a pretreatment unit for separation of nucleic acids from lysates, a preconcentration unit for concentration of isolated nucleic acids and a sensing unit localized at a designated position on the chip for specific detection of the target nucleic acid. The platform is based on various electrokinetic phenomena exhibited by ion exchange membranes in a DC electrical field that allow them to serve as molecular filters, analyte preconcentrators and sensors. In this manuscript, we describe each unit of the integrated chip separately and show specific detection of a microRNA (miRNA 146a) biomarker associated with oral cancer as a proof-of-concept experiment. This platform technology can easily be extended to other targets of interest by optimizing the properties of the ion exchange membranes and the specific probes functionalized onto the sensors., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The present work is aimed to develop and optimize pulsatile delivery during dissolution of an improved formulation of valsartan to coordinate the drug release with circadian rhythm. Preliminary studies suggested that β cyclodextrin could improve the solubility of valsartan and showed AL type solubility curve. A 1:1 stoichiometric ratio of valsartan to β cyclodextrin was revealed from phase solubility studies and Job's plot. The prepared complex showed significantly better dissolution efficiency (p < 0.05) compared to pure drug, which could be due to the formation of inclusion complex as revealed from FTIR and DSC studies. Continuous dissolution-absorption studies revealed that absorption of drug from valsartan β cyclodextrin complex was significantly higher (p < 0.05) compared to pure drug, in second part press-coated tablets of valsartan β cyclodextrin complex were subsequently prepared and application of the Plackett-Burman screening design revealed that HPMC K4M and EC showed significant effect on lag time. A 3(2) full factorial design was used to measure the response of HPMC K4M and EC on lag time and time taken for 90% drug release (T90). The optimized batch prepared according to the levels obtained from the desirability function had a lag time of 6 h and consisted of HPMC K4M:ethylcellulose in a 1:1.5 ratio with 180 mg of coating and revealed a close agreement between observed and predicted value (R(2 )= 0.9694).

Men have a higher age-adjusted death rate from many of the leading causes of death, compared with women. Avoidance of health care and unhealthy behavior contribute to premature death among men. The Lahey Clinic recently initiated a program, the Men's Educational Group Appointment (MEGA), which capitalizes on the potential benefits of group dynamics in an effort to educate men about preventative health. We hypothesized that putting men into a group setting for the educational portion of the visit would improve information exchange and patient learning. During 12 months, 261 men between the ages of 22 and 67 were evaluated. A survey designed to address both patient satisfaction and patients' perceptions regarding how much they learned was administered to all patients following the MEGA session. We identified high patient satisfaction with the MEGA model. This study illustrates the potential utility of the group model for improving patient education regarding health maintenance among men.

Etoricoxib is a cyclooxygenase 2 (COX-2) inhibitor that selectively inhibits the COX-2 enzyme and decreases the incidences of side effects associated with these agents. It is commonly prescribed for acute pain, gouty arthritis, and rheumatoid arthritis. Conventional tablets of etoricoxib are not capable of rapid action, which is required for faster drug effect onset and immediate relief from pain. Thus, the aim of the present investigation is to formulate orally disintegrating tablets (ODTs) of etoricoxib. A combination of the superdisintegrants with a sublimation technique was used to prepare the tablets. Tablets were prepared using a direct compression method employing superdisintegrants such as low substituted hydroxylpropyl methyl cellulose (L-HPMC), low substituted hydroxyl-propyl cellulose (L-HPC), crospovidone, croscarmellose sodium, and sodium starch glycolate. Tablets of etoricoxib prepared using L-HPC exhibited the least friability and disintegration time (approximately 65 s). To decrease the disintegration time further, a sublimation technique was used along with the superdisintegrants for the preparation of ODTs. The use of sublimating agents including camphor, menthol, and thymol was explored. The addition of camphor lowered the disintegration time (approximately 30 s) further, but the percent friability was increased. A 3(2) full factorial design was employed to study the joint influence of the amount of superdisintegrant (L-HPC) and the amount of sublimating agent (camphor) on the percent of friability and the disintegration time. The results of multiple linear regression analysis revealed that for obtaining an effective ODT of etoricoxib, higher percentages of L-HPC and camphor should be used. Checkpoint batches were prepared to validate the evolved mathematical model. A response surface plot is also presented to graphically represent the effect of the independent variables on the percent of friability and the disintegration time. The approach using the optimization technique helped to produce a detailed understanding of the effects of formulation parameters.

The ability to exercise precise spatial and temporal control over cell-surface interactions is an important prerequisite to the assembly of multi-cellular constructs serving as in vitro mimics of native tissues. In this study, photolithography and wet etching techniques were used to fabricate individually addressable indium tin oxide (ITO) electrodes on glass substrates. The glass substrates containing ITO microelectrodes were modified with poly(ethylene glycol) (PEG) silane to make them protein and cell resistive. Presence of insulating PEG molecules on the electrode surface was verified by cyclic voltammetry employing potassium ferricyanide as a redox reporter molecule. Importantly, the application of reductive potential caused desorption of the PEG layer, resulting in regeneration of the conductive electrode surface and appearance of typical ferricyanide redox peaks. Application of reductive potential also corresponded to switching of ITO electrode properties from cell non-adhesive to cell-adhesive. Electrochemical stripping of PEG-silane layer from ITO microelectrodes allowed for cell adhesion to take place in a spatially defined fashion, with cellular patterns corresponding closely to electrode patterns. Micropatterning of several cell types was demonstrated on these substrates. In the future, the control of the biointerfacial properties afforded by this method will allow to engineer cellular microenvironments through the assembly of three or more cell types into a precise geometric configuration on an optically transparent substrate.