Safety and Pharmacokinetics of a Ciprofloxacin and Azithromycin Stent for Chronic Rhinosinusitis.

OBJECTIVES: Previously, we developed a novel double-coated sinus stent containing ciprofloxacin (inner layer) and azithromycin (outer layer) (CASS), but released drug concentrations were found to be insufficient for clinical usage. Our objectives are to improve drug release of CASS and assess safety and pharmacokinetics in rabbits. METHODS: Dip coating was used to create the CASS with 2 mg ciprofloxacin and 5 mg azithromycin. A uniformed double coating was assessed with scanning electron microscopy (SEM), and the release patterns of both drugs and lactate dehydrogenase (LDH) assay were evaluated over 14 days in vitro. Safety, tolerability, and pharmacokinetics of the CASS were tested in rabbits through insertion into the maxillary sinus and evaluated with nasal endoscopy, CT scans, histology, blood counts and chemistries, and in vivo drug release. RESULTS: SEM confirmed the uniformity of the dual coating of ciprofloxacin and azithromycin, and thickness (µm) was found to be 14.7 ± 2.4 and 28.1 ± 4.6, respectively. The inner coated ciprofloxacin showed a sustained release over 14 days (release %) when soaked in saline solution (day 7, 86.2 ± 3.4 vs. day 14,99.2 ± 5.1). In vivo analysis showed that after 12 days, 78.92 ± 7.67% of CP and 84.12 ± 0.45% of AZ were released into the sinus. There were no significant differences in body weight, white blood cell counts, and radiographic changes before and after CASS placement. No significant histological changes were observed compared to the contralateral control side. CONCLUSION: Findings suggest that the CASS is an effective method for delivering therapeutic levels of antibiotics. Further studies are needed to validate efficacy in a preclinical sinusitis model. LEVEL OF EVIDENCE: N/A Laryngoscope, 2024.

US public opinion about reproductive health care in school-based health centers.

OBJECTIVES: This study aimed to examine public support for the provision of seven reproductive health services in school-based health centers, including pregnancy testing, over-the-counter contraceptives, prescription (Rx) contraceptives, sexually transmitted disease testing, sexually transmitted disease treatment, gynecological examinations, sexual violence counseling, and an index measure combining all services. STUDY DESIGN: We administered a large national online survey (N = 4196, response rate 31%) of US adults using Lucid, a large, internet-based, opt-in panel to assess public attitudes about offering sexual and reproductive health services in school-based health centers. We then used t tests and weighted linear regression models to carry out our study objectives. RESULTS: Unadjusted analysis revealed that 60% of respondents supported the provision of all reproductive health services (combined) at school-based health centers. Regression analysis based on the index measure suggested that individuals identifying as Trump voters (p-value = 0.00) or conservatives (p-value = 0.00) reported the lowest support, while those identifying as liberal (p-value = 0.00) reported the highest support, controlling for demographic and health characteristics. CONCLUSIONS: Respondents overwhelmingly support the provision of reproductive health services at school-based health centers, including pregnancy testing, over-the-counter contraceptives, prescription contraceptives, testing and treatment for sexually transmitted infections, and sexual violence counseling. IMPLICATIONS: Adolescence is an important stage for sexual maturation, and access to appropriate sexual and reproductive health services can support healthy development into adulthood. Findings suggest that most respondents support the provision of reproductive health services at school-based health centers while there are important factors that influence public support.

What the Evolution of 1332 Waivers Tells Us about Their Innovative Potential.

Section 1332 of the Affordable Care Act (ACA) provides states unprecedented flexibility to alter federal health policy. The authors analyze state waiver activity from 2019 to 2023, applying a comparative approach to understand waivers proposed by Georgia, Colorado, Washington, Oregon, and Nevada. Much of the waiver activity during this period focused on reinsurance programs. During the Trump administration, the most innovative waiver application was from Georgia, which sought to restructure and decentralize its individual market, moving away from the framework established by the ACA. While the Biden administration suspended Georgia's efforts, Democratic-led states have focused implementing waiver programs supporting and expanding on the ACA. This has included adopting public-option insurance plans offered by private insurers and expanding eligibility for qualified health plans for previously ineligible groups. The authors' analysis offers insights into contemporary health politics, policy durability, and the role of the administrative presidency.

Hypoxia-induced cystic fibrosis transmembrane conductance regulator dysfunction is a universal mechanism underlying reduced mucociliary transport in sinusitis.

INTRODUCTION: Hypoxia due to sinus obstruction is a major pathogenic mechanism leading to sinusitis. The objective of the current study is to define the electrophysiologic characteristics of hypoxia in vitro and in vivo. METHODS: Cystic fibrosis bronchoepithelial cells expressing wild-type cystic fibrosis transmembrane conductance regulator (CFTR) and human sinonasal epithelial cells were exposed to 1% or atmospheric O2 for 24 h. Time-dependent production of cytoplasmic free radicals was measured. Cells were subjected to Ussing chamber and patch clamp technique where CFTR currents were recorded in whole-cell and cell-attached mode for single channel studies. Indices of mucociliary transport (MCT) were measured using micro-optical coherence tomography. In a rabbit hypoxic maxillary sinus model, tissue oxygenation, relative mRNA expression of HIF-1α, pH, sinus potential difference (SPD), and MCT were determined. RESULTS: Ussing chamber (p < 0.05), whole-cell (p < 0.001), and single channel patch-clamp (p < 0.0001) showed significant inhibition of Cl- currents in hypoxic cells. Cytoplasmic free radicals showed time-dependent elevation peaking at 4 h (p < 0.0001). Airway surface liquid (p < 0.0001), periciliary liquid (p < 0.001), and MCT (p < 0.01) were diminished. Co-incubation with the free radical scavenger glutathione negated the impact of hypoxia on single channel currents and MCT markers. In sinusitis rabbits, mucosa exhibited low tissue oxygenation (p < 0.0001), increased HIF1α mRNA (p < 0.05), reduced pH (p < 0.01), and decreased MCT (p < 0.001). SPD measurements demonstrated markedly diminished transepithelial Cl- transport (p < 0.0001). CONCLUSION: Hypoxia induces severe CFTR dysfunction via free radical production causing reduced MCT in vitro and in vivo. Improved oxygenation is critical to reducing the impact of persistent mucociliary dysfunction.

Glutathione and bicarbonate nanoparticles improve mucociliary transport in cystic fibrosis epithelia.

INTRODUCTION: Cystic fibrosis (CF) airway disease is characterized by thick mucus and impaired mucociliary transport (MCT). Loss of functional cystic fibrosis transmembrane receptor (CFTR) leads to acidification and oxidation of airway surface mucus. Replacing bicarbonate (HCO3 - ) topically fails due to rapid reabsorption and neutralization, while the scavenging antioxidant, glutathione sulfhydryl (GSH), is also rapidly degraded. The objective of this study is to investigate GSH/NaHCO3 nanoparticles as novel strategy for CF airway disease. METHODS: GSH/NaHCO3 poly (lactic-co-glycolic acid) nanoparticles were tested on primary CF (F508del/F508del) epithelial cultures to evaluate dose-release curves, surface pH, toxicity, and MCT indices using micro-optical coherence tomography. In vivo tests were performed in three rabbits to assess safety and toxicity. After 1 week of daily injections, histopathology, computed tomography (CT), and blood chemistries were performed and compared to three controls. Fluorescent nanoparticles were injected into a rabbit with maxillary sinusitis and explants visualized with confocal microscopy. RESULTS: Sustained release of GSH and HCO3 - with no cellular toxicity was observed over 2 weeks. Apical surface pH gradually increased from 6.54 ± 0.13 (baseline) to 7.07 ± 0.10 (24 h) (p < 0.001) and 6.87 ± 0.05 at 14 days (p < 0.001). MCT, ciliary beat frequency, and periciliary liquid were significantly increased. When injected into the maxillary sinuses of rabbits, there were no changes to histology, CT, or blood chemistries. Nanoparticles penetrated rabbit sinusitis mucus on confocal microscopy. CONCLUSION: Findings suggest that GSH/NaHCO3 - nanoparticles are a promising treatment option for viscous mucus in CF and other respiratory diseases of mucus obstruction such as chronic rhinosinusitis.

Red ginseng aqueous extract improves mucociliary transport dysfunction and histopathology in CF rat airways.

BACKGROUND: We previously discovered that Korean red ginseng aqueous extract (RGAE) potentiates the TMEM16A channel, improved mucociliary transport (MCT) parameters in CF nasal epithelia in vitro, and thus could serve as a therapeutic strategy to rescue the MCT defect in cystic fibrosis (CF) airways. The hypothesis of this study is that RGAE can improve epithelial Cl- secretion, MCT, and histopathology in an in-vivo CF rat model. METHODS: Seventeen 4-month old CFTR-/- rats were randomly assigned to receive daily oral control (saline, n = 9) or RGAE (Ginsenosides 0.4mg/kg/daily, n = 8) for 4 weeks. Outcomes included nasal Cl- secretion measured with the nasal potential difference (NPD), functional microanatomy of the trachea using micro-optical coherence tomography, histopathology, and immunohistochemical staining for TMEM16a. RESULTS: RGAE-treated CF rats had greater mean NPD polarization with UTP (control = -5.48 +/- 2.87 mV, RGAE = -9.49 +/- 2.99 mV, p < 0.05), indicating, at least in part, potentiation of UTP-mediated Cl- secretion through TMEM16A. All measured tracheal MCT parameters (airway surface liquid, periciliary liquid, ciliary beat frequency, MCT) were significantly increased in RGAE-treated CF rats with MCT exhibiting a 3-fold increase (control, 0.45+/-0.31 vs. RGAE, 1.45+/-0.66 mm/min, p < 0.01). Maxillary mucosa histopathology was markedly improved in RGAE-treated cohort (reduced intracellular mucus, goblet cells with no distention, and shorter epithelial height). TMEM16A expression was similar between groups. CONCLUSION: RGAE improves TMEM16A-mediated transepithelial Cl- secretion, functional microanatomy, and histopathology in CF rats. Therapeutic strategies utilizing TMEM16A potentiators to treat CF airway disease are appropriate and provide a new avenue for mutation-independent therapies.

Schools at the center of a public health emergency: leveraging schools for pediatric COVID-19 vaccination.

The U.S. Food and Drug Administration's expansion of COVID-19 vaccine eligibility in 2021 to include children presented opportunities and challenges to ensure widespread access. Children, and especially adolescents, were a crucial target population to reduce community positivity rates and support a resumption of in-person academics. Though existing school-based vaccination programs have demonstrated success in improving vaccination rates on an individual school level, best practice strategies for employing mass vaccination programs quickly in response to public health emergencies have yet to be identified. Through established partnerships, School Health Services at Nationwide Children's Hospital led a collaborative effort to employ a rapid, onsite school vaccination strategy across Franklin County for all eligible students. This collaboration resulted in a significant increase in vaccine access carried out through on-site vaccination clinics established in 20 local public and private school districts. Key strategies identified through the process included collaboration with school districts, local hospitals, and the public health department; calibrating program size to each site and number of vaccines needed; and coordination of team member roles. At the same time, experience with the effort also underscored key challenges and opportunities that future programs should consider, especially when operating in public health emergencies. School-based community health approaches targeting adolescents can increase vaccination rates, and can be successfully led by children's health systems in concert with public health departments and schools. At the same time, entities undertaking such efforts must plan in advance to ensure that partnerships can be effectively established with clear protocols for efficient and open communication, which is essential for overcoming barriers in access to healthcare services.

An Imperfect Space: Logistical Considerations in School-Based Health Centers.

BACKGROUND: From a range of perspectives, scholars have demonstrated the value of school-based health centers (SBHCs) in recent decades, but few studies have examined the logistics of establishing SBHCs. METHODS: Semi-structured interviews were conducted with 9 hospital and 6 school employees involved in a network of SBHCs. After common themes were identified, cluster analysis was performed. Finally, quotes were identified within each thematic cluster for further qualitative analysis. RESULTS: The most prominent themes were (1) differences in physical space (between schools and clinical settings), (2) collaboration and communication, and (3) privacy and compliance. IMPLICATIONS FOR SCHOOL HEALTH POLICY, PRACTICE, AND EQUITY: This study points to several high yield considerations for the practice of SBHCs. First, we identified three distinct needs: (1) clear funding streams for construction costs for health services on school grounds, (2) improved understanding of SBHC space needs, and (3) blueprints for collaborating within SBHCs. Second, this study points to a future in which new-build and renovated schools should include space for SBHCs. CONCLUSIONS: This qualitative thematic analysis provides a picture of health and educational professionals engaged in creative, collaborative, and adaptive work to meet children's health care needs within SBHCs, but also highlights the challenges of navigating physical space, compliance, and collaboration within SBHCs.

The Paradoxical Politics of Community Health Centers from the Great Society to the COVID-19 Pandemic.

CONTEXT: Although community health centers (CHCs) arose in the 1960s as part of a Democratic policy push committed to social justice, subsequent support has been shaped by paradoxical politics wherein Republican and Democratic support for CHCs continually morphed in response to changes in the health policy landscape. METHODS: Drawing on the CHC literature and empirical examples from firsthand accounts and reporting, this article explains CHCs' curious historical development from 1965 to the present. FINDINGS: Both Republicans and Democrats have calibrated their support for CHCs in response to a broader set of political considerations, from antiwelfare policy commitments to aspirations of establishing a national health care plan. CONCLUSIONS: CHCs have proven to be a politically malleable policy tool within the broader context of American health care policy. The COVID-19 pandemic raised new questions about CHCs' sustainability and future, but CHCs will continue to play a critical role in providing health care access to underserved populations. They also will continue to be an attractive bipartisan policy option within the larger framework of US health policy.

Social Determinants of Health as a Lens for Understanding Local News Reporting.

While scholars have long examined media bias, few studies have systematically examined how media represents health within American urban neighborhoods. Drawing on a qualitative analysis of 10 years of news articles of one Ohio neighborhood, the authors apply a social determinants of health (SDOH) lens to the coverage of one urban newspaper. The study's aim is to understand what a SDOH approach might tell us about local and ongoing coverage of historically challenged neighborhoods. Findings reinforce those of previous studies from health communication and media studies which document a disproportionate emphasis on crime, but also push the conversation further to show how the health aspects of housing and food instability, unemployment, and non-crime safety concerns, are often elided in news coverage. The authors argue that the SDOH lens affords journalists a framework for ensuring that their reporting adequately captures the drivers of poor health in American urban neighborhoods.

A Thematic Analysis of Osteopathic Physicians' Identities and Experiences in North American Professional Sports.

Objective: This interview-based thematic analysis examines the evolving professional identities and practices of osteopathic physicians (DOs) in North American professional sports (baseball, basketball, football, hockey, and soccer) to understand the extent to which DOs employ osteopathic-specific skill sets in their work with player-patients. In addition, the study sought to understand the prevalence of professional bias, interprofessional dynamics between DOs and other health professionals, and other factors such as management. Methods: This qualitative, interview-based study is grounded in twelve semi-structured interviews with 41% of DOs (all nonsurgical, primary care sports medicine trained) working with North American professional sports teams. Interviews were transcribed and coded to identify key themes and representative quotes. Results: Findings suggest that DOs believe their training and philosophical orientation positions them well to make important contributions to serving the medical needs of professional sports teams. At the same time, DOs are careful about championing an osteopathically-specific approach to patient care, such as evoking osteopathic principles of care or techniques such as Osteopathic Manipulative Medicine. This is the case for several reasons, the most important of which is a strong drive toward collaboration and collegiality within professional sports medicine teams. Conclusion: This study finds that in navigating the complexities of osteopathic identity, DOs working in professional sports are proud of their osteopathic orientation and report experiencing little discrimination, but also downplay what has historically distinguished their practice from that of other healthcare professionals. These findings have consequences for how scholars think about emerging professional identities in sports medicine, generally, as well as the fast-growing profession of osteopathic medicine specifically.

Spatial epidemiology of hemorrhagic disease in Illinois wild white-tailed deer.

Epizootic hemorrhagic disease (EHD) and bluetongue (BT) are vector-borne viral diseases that affect wild and domestic ruminants. Clinical signs of EHD and BT are similar; thus, the syndrome is referred to as hemorrhagic disease (HD). Syndromic surveillance and virus detection in North America reveal a northern expansion of HD. High mortalities at northern latitudes suggest recent incursions of HD viruses into northern geographic areas. We evaluated the occurrence of HD in wild Illinois white-tailed deer from 1982 to 2019. Our retrospective space-time analysis identified high-rate clusters of HD cases from 2006 to 2019. The pattern of northward expansion indicates changes in virus-host-vector interactions. Serological evidence from harvested deer revealed prior infection with BTV. However, BTV was not detected from virus isolation in dead deer sampled during outbreaks. Our findings suggest the value of capturing the precise geographic location of outbreaks, the importance of virus isolation to confirm the cause of an outbreak, and the importance of expanding HD surveillance to hunter-harvested wild white-tailed deer. Similarly, it assists in predicting future outbreaks, allowing for targeted disease and vector surveillance, helping wildlife agencies communicate with the public the cause of mortality events and viral hemorrhagic disease outcomes at local and regional scales.

In vitro evaluation of a novel oxygen-generating biomaterial for chronic rhinosinusitis therapy.

BACKGROUND: Hypoxia due to closure at the ostiomeatal complex is widely considered one of the major pathogenic mechanisms leading to chronic inflammation in chronic rhinosinusitis (CRS). The objective of this study was to develop and characterize an oxygen-generating biomaterial (OGB) as an innovative treatment strategy for CRS. METHODS: An OGB was fabricated by coating hydrophobic beeswax (BW, 15mg or 30mg) on the surface of calcium peroxide - catalase complex (CPO-CA, 30mg) and characterized using scanning electron microscopy (SEM). In vitro releases of both oxygen and hydrogen peroxide (H2 O2 ) were spectrophotometrically quantified, and cytotoxicity in human sinonasal epithelial cells (HSNECs) was evaluated. The influence of OGB on transepithelial Cl- secretion was also determined by pharmacologically manipulating HSNECs, cultured under hypoxic conditions, in Ussing chambers. RESULTS: Three groups of OGBs: (1) CPO only; (2) CPO coated with CA and BW (1:1 ratio, CPO-CA(1)-BW(1)); and (3) CPO coated with CA and BW (1:0.5 ratio, CPO-CA(1)-BW(0.5) were analyzed for accumulated oxygen release over 7 days: highest release (mmol/mg) was observed in CPO-CA(1)-BW(1) = 0.11 ± 0.003, followed by CPO-CA(1)-BW(0.5) = 0.08 ± 0.010, and CPO = 0.05 ± 0.004 (p < 0.0001). H2 O2 production (mM) was significantly higher in CPO (1.87 ± 0.50) compared to CPO-CA (1)-BW(1) (0.00 ± 0.00) (p < 0.001) after 24 h. CPO-CA(1)-BW(1) showed significantly reduced cytotoxicity and increased Cl- transport compared to the CPO group. CONCLUSION: A novel OGB (CPO-CA-BW complex) exhibited sustained oxygen release over 7 days without significant cytotoxicity after 24 h in vitro. Preclinical studies evaluating the efficacy of OGB in CRS are warranted, especially for potential therapy in an obstruction-based CRS model.

Ivacaftor restores delayed mucociliary transport caused by Pseudomonas aeruginosa-induced acquired cystic fibrosis transmembrane conductance regulator dysfunction in rabbit nasal epithelia.

BACKGROUND: Abnormal chloride (Cl- ) transport dehydrates airway surface liquid (ASL) in sinonasal epithelium leading to mucus stasis and chronic rhinosinusitis. As an experimental epithelium, rabbit tissue provides an excellent representation of human sinus disease, and the rabbit sinusitis model is both established and well suited for therapeutic interventions in vivo. Our objective in this study was to evaluate whether ivacaftor reverses the consequences of Pseudomonas aeruginosa-induced acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. METHODS: Rabbit nasal cavities were assessed for responsiveness to ivacaftor in vivo (by nasal potential difference [NPD] assay). Rabbit nasal epithelial (RNE) cultures were incubated with an ultrafiltrate of P aeruginosa (PAO1 strain) for 4 hours and tested for acquired CFTR dysfunction. Markers of mucociliary function, including airway surface liquid depth (ASL), periciliary liquid depth (PCL), ciliary beat frequency (CBF), and mucociliary transport (MCT), were measured by micro-optical coherence tomography (µOCT) after PAO1 and/or ivacaftor incubation. RESULTS: Ivacaftor resulted in a significant mean NPD polarization of 21.8 ± 2.1 mV, which was significantly greater than that seen in the low Cl- control (12.9 ± 1.3; p = 0.01). PAO1 exposure induced a state of acquired CFTR dysfunction in rabbit nasal epithelium as measured by forskolin-stimulated short-circuit current (ISC ) (control, 37.0 ± 1.1 µA/cm2 ; PAO1, 24.4 ± 1.1 µA/cm2 ; p < 0.001). RNE cultures exposed to PAO1 had inhibited mucociliary function, whereas coincubation with ivacaftor restored mucociliary clearance, as measured by µOCT. CONCLUSION: In rabbit nasal epithelium, ivacaftor robustly stimulates CFTR-mediated Cl- secretion and normalizes ASL and CBF in PAO1-induced acquired CFTR dysfunction. Preclinical testing of CFTR potentiators as therapy for P aeruginosa rabbit sinusitis is planned.

Building trust in American hospital-community development projects: a scoping review.

Although it has become increasingly common for hospitals to engage in development projects aimed at improving the social determinants of health in surrounding communities, scholarly literature examining the establishment of trust between hospitals and communities is sparse. Because of an extensive and complex history of abuse suffered by marginalized populations at the hands of medical institutions, trust building is critical to the pursuit of equitable health outcomes in these communities. A scoping review was conducted to assess the current base of knowledge for building trust between hospital systems and community members. The review identified only 13 relevant articles addressing this topic, centered on six key themes: with whom to form partnerships; how to form partnerships; conceptualizing and defining trust; questions about investment and hiring; effective communication with communities; and, understanding communities.

LPS decreases CFTR open probability and mucociliary transport through generation of reactive oxygen species.

Lipopolysaccharide (LPS) serves as the interface between gram-negative bacteria (GNB) and the innate immune response in respiratory epithelial cells (REC). Herein, we describe a novel biological role of LPS that permits GNB to persist in the respiratory tract through inducing CFTR and mucociliary dysfunction. LPS reduced cystic fibrosis transmembrane conductance regulater (CFTR)-mediated short-circuit current in mammalian REC in Ussing chambers and nearly abrogated CFTR single channel activity (defined as forskolin-activated Cl- currents) in patch clamp studies, effects of which were blocked with toll-like receptor (TLR)-4 inhibitor. Unitary conductance and single-channel amplitude of CFTR were unaffected, but open probability and number of active channels were markedly decreased. LPS increased cytoplasmic and mitochondrial reactive oxygen species resulting in CFTR carbonylation. All effects of exposure were eliminated when reduced glutathione was added in the medium along with LPS. Functional microanatomy parameters, including mucociliary transport, in human sinonasal epithelial cells in vitro were also decreased, but restored with co-incubation with glutathione or TLR-4 inhibitor. In vivo measurements, following application of LPS in the nasal cavities showed significant decreases in transepithelial Cl- secretion as measured by nasal potential difference (NPD) - an effect that was nullified with glutathione and TLR-4 inhibitor. These data provide definitive evidence that LPS-generated reactive intermediates downregulate CFTR function in vitro and in vivo which results in cystic fibrosis-type disease. Findings have implications for therapeutic approaches intent on stimulating Cl- secretion and/or reducing oxidative stress to decrease the sequelae of GNB airway colonization and infection.

Korean Red Ginseng aqueous extract improves markers of mucociliary clearance by stimulating chloride secretion.

BACKGROUND: Abnormal chloride (Cl-) transport has a detrimental impact on mucociliary clearance in both cystic fibrosis (CF) and non-CF chronic rhinosinusitis. Ginseng is a medicinal plant noted to have anti-inflammatory and antimicrobial properties. The present study aims to assess the capability of red ginseng aqueous extract (RGAE) to promote transepithelial Cl- secretion in nasal epithelium. METHODS: Primary murine nasal septal epithelial (MNSE) [wild-type (WT) and transgenic CFTR-/-], fisher-rat-thyroid (FRT) cells expressing human WT CFTR, and TMEM16A-expressing human embryonic kidney cultures were utilized for the present experiments. Ciliary beat frequency (CBF) and airway surface liquid (ASL) depth measurements were performed using micro-optical coherence tomography (µOCT). Mechanisms underlying transepithelial Cl- transport were determined using pharmacologic manipulation in Ussing chambers and whole-cell patch clamp analysis. RESULTS: RGAE (at 30µg/mL of ginsenosides) significantly increased Cl- transport [measured as change in short-circuit current (ΔISC = µA/cm2)] when compared with control in WT and CFTR-/- MNSE (WT vs control = 49.8±2.6 vs 0.1+/-0.2, CFTR-/- = 33.5±1.5 vs 0.2±0.3, p < 0.0001). In FRT cells, the CFTR-mediated ΔISC attributed to RGAE was small (6.8 ± 2.5 vs control, 0.03 ± 0.01, p < 0.05). In patch clamp, TMEM16A-mediated currents were markedly improved with co-administration of RGAE and uridine 5-triphosphate (8406.3 +/- 807.7 pA) over uridine 5-triphosphate (3524.1 +/- 292.4 pA) or RGAE alone (465.2 +/- 90.7 pA) (p < 0.0001). ASL and CBF were significantly greater with RGAE (6.2+/-0.3 µm vs control, 3.9+/-0.09 µm; 10.4+/-0.3 Hz vs control, 7.3 ± 0.2 Hz; p < 0.0001) in MNSE. CONCLUSION: RGAE augments ASL depth and CBF by stimulating Cl- secretion through CaCC, which suggests therapeutic potential in both CF and non-CF chronic rhinosinusitis.

Do State Opioid Policies Influence Nonprofit Hospitals' Decisions to Address Substance Abuse in Their Communities?

The U.S. epidemic of opioid abuse calls for broad collaboration between a wide range of health care institutions and the various levels of government. Through the community benefit programs they provide, nonprofit hospitals are well positioned to be key partners in local efforts. Although substance abuse appears on approximately 90% of the most recent community health needs assessments completed by hospitals, many hospitals are not addressing substance abuse in their programmatic efforts. Given wide state variation in policies to combat opioid abuse, we assess whether state leadership to address the opioid crisis influences hospital decisions to invest in substance abuse programs. Our findings suggest that several key state policies are related to hospital investments in substance abuse initiatives. To capitalize on the community benefit responsibilities of local hospitals, policies that provide specific direction for and engagement with local hospitals may increase cooperation and investments to address substance abuse.

Azithromycin and ciprofloxacin inhibit interleukin-8 secretion without disrupting human sinonasal epithelial integrity in vitro.

BACKGROUND: We recently developed a ciprofloxacin and azithromycin sinus stent (CASS) to target recalcitrant infections in chronic rhinosinusitis (CRS). The objective of this study was to evaluate the anti-inflammatory activity of azithromycin released from the CASS and assess the impact on the integrity and function of primary human sinonasal epithelial cells (HSNECs). METHODS: Pseudomonas aeruginosa lipopolysaccharide (LPS)-stimulated HSNECs were treated with azithromycin and/or ciprofloxacin at concentrations attainable from CASS release. Interleukin-8 (IL-8) secretion was quantified by enzyme-linked immunosorbent assay (ELISA). Epithelial integrity (transepithelial resistance [TEER], paracellular permeability [fluorescein isothiocyanate-labeled dextran], lactate dehydrogenase [LDH] assays) and function (ciliary beat frequency [CBF]) were also evaluated. RESULTS: Azithromycin significantly reduced secreted IL-8 from P. aeruginosa LPS-stimulated HSNECs at all concentrations tested (mean ± standard deviation; control = 5.77 ± 0.39 ng/mL, azithromycin [6 µg/mL] = 4.58 ± 0.40 ng/mL, azithromycin [60 µg/mL] = 4.31 ± 0.06, azithromycin [180 µg/mL] = 4.27 ± 0.26 ng/mL, p < 0.05). Co-incubation with azithromycin (6 µg/mL) and ciprofloxacin (2.4 µg/mL) in LPS-stimulated HSNECs also displayed a significant reduction in secreted IL-8 when compared to P. aeruginosa LPS alone (co-treatment = 4.61 ± 0.29 ng/mL, P. aeruginosa LPS = 7.35 ± 0.89 ng/mL, p < 0.01). The drugs did not negatively impact TEER, paracellular permeability, LDH release, or CBF, indicating retention of cell integrity and function. CONCLUSION: Azithromycin decreased P. aeruginosa LPS IL-8 production in HSNECs at drug concentrations attainable with sustained release of azithromycin from the CASS. In addition to antibacterial activity, anti-inflammatory properties of the CASS should provide further benefit for patients with recalcitrant CRS.