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Abstract Background Evidence suggests that the inflammatory events in the acute phase of spinal cord injury (SCI) exacerbate the initial trauma to the cord leading to poor functional recovery. As a result, minimizing the detrimental aspects of the inflammatory response after SCI is a promising treatment strategy. In this regard, immunoglobulin G (IgG) from pooled human serum is a promising treatment candidate. Due to its putative, though poorly characterized immuno-modulatory effects, IgG has been used clinically to treat neuroinflammatory disorders such as Guillain-Barré syndrome, but its effects in neurotrauma remain largely unexplored. Methods This study examines the potential neuroprotective effects of IgG in a well-characterized cervical model of SCI. Female Wistar rats were subject to moderate-severe clip compression injury at the C7-T1 level. IgG (0.4 g/kg) or saline was injected intravenously to randomly selected animals at 15 min post SCI. At several time points post SCI, biochemical assays, histology and immunohistochemistry analyses, and neurobehavioral assessments were used to examine the neuroprotective effects of IgG at the molecular, cellular, and neurobehavioral levels. Results We found that intravenous treatment of IgG following acute clip-compression SCI at C7-T1 significantly reduced two important inflammatory cytokines: interleukin (IL)-1β and IL-6. This early reduction in pro-inflammatory signaling was associated with significant reductions in neutrophils in the spinal cord and reductions in the expression of myeloperoxidase and matrix metalloproteinase-9 in the injured spinal cord at 24 h after SCI. These beneficial effects of IgG were associated with enhanced tissue preservation, improved neurobehavioral recovery as measured by the BBB and inclined plane tests, and enhanced electrophysiological evidence of central axonal conduction as determined by motor-evoked potentials. Conclusion The findings from this study indicate that IgG is a novel immuno-modulatory therapy which shows promise as a potential treatment for SCI.

Abstract Background Spinal cord injury (SCI) is a devastating condition with substantial functional and social morbidity. Previous research has established that the neuroinflammatory response plays a significant role in cord damage post-SCI. However, global immunosuppressive therapies have demonstrated mixed results. As a result, more specific therapies modulating inflammation after injury are needed. In this regard, research into cytokine signaling has demonstrated that cytokines of the gp130 family including IL-6 and leukemia inhibitory factor (LIF) play key roles in mediating damage to the spinal cord. Since members of the gp130 family all share a common signal transduction pathway via the JAK/STAT system, we performed the first study of a relatively new member of the gp130 family, IL-11, in SCI. Methods A validated clip-compression mouse model of SCI was used to assess for temporal changes in expression of IL-11 and its receptor, IL-11Rα, post-SCI. To elucidate the role of IL-II in the pathophysiology of SCI, we compared differences in locomotor recovery (Basso Mouse Score; CatWalk), electrophysiological spinal cord signaling, histopathology, and the acute inflammatory neutrophil response in IL-11Rα knockouts with littermate wild-type C57BL/6 mice. Results We found an increase in gene expression of IL-11 in the spinal cord to a peak at twenty-four hours post-SCI with increases in IL-11Rα gene expression, peaking at seven days post-SCI. In spite of clear changes in the temporal expression of both IL-11 and its receptor, we found that there were no significant differences in motor function, electrophysiological signaling, histopathology, or neutrophil infiltration into the spinal cord between wild-type and knockout mice. Conclusions This is the first study to address IL-11 in SCI. This study provides evidence that IL-11 signaling may not play as significant a role in SCI as other gp130 cytokines, which will ideally guide future therapy design and the signaling pathways those therapies target.

Background/aim: Skin wound healing is a physiological process restoring the structural and functional integrity of injured skin. During this process, wound management preventing bacterial infection and complications is important for the regeneration of skin layers and adnexa, as well as the protective function of the skin. Therefore, the development of an effective ointment to promote wound healing without complications is beneficial., Materials and Methods: This study developed Raepenol™ cream, comprising a base cream and natural compounds including paeonol, D-panthenol and extract of Centella asiatica, and assessed its therapeutic effect in wound healing. A rat model of skin wound healing and a mouse model of imiquimod-induced pruritus were employed. The effect of Raepenol™ cream was evaluated by wound size and histological analysis, including the integrity of skin structures and inflammatory response., Results: Raepenol™ cream treatment effectively restored the structural integrity of the skin in rats, including wound closure, regeneration of skin adnexa, and reconstitution of collagen, comparable to commercial ointment. Additionally, Raepenol™ cream significantly suppressed pruritus by inhibiting mast cell infiltration or retention in the inflammatory site of mouse ears., Conclusion: Raepenol™ cream effectively promoted wound healing and relieved pruritus in animal models. These results suggest that it could be a promising option for wound care and pruritus relief, offering potential advantages over current ointments., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Individuals with gender dysphoria do not identify with their sex assigned at birth and face societal and cultural challenges, leading to increased risk for depression, anxiety, and suicide. Gender dysphoria is a DSM-5 diagnosis but is not necessary for transition therapy. Additionally, individuals with gender dysphoria or who identify as gender diverse/nonconforming may experience "minority stress" from increased discrimination, leading to a greater risk for mental health problems. This study aimed to identify possible health disparities in patients hospitalized for depression with gender dysphoria across the United States. Depression was selected because patients with gender dysphoria are at an increased risk for it. Various patient and hospital-related factors are explored for their association with changes in healthcare utilization for patients hospitalized with depression., Methods: The National Inpatient Sample was used to identify nationwide patients with depression ( n  = 378,552, weighted n  = 1,892,760) from 2016 to 2019. We then examined the characteristics of the study sample and investigated how individuals' gender dysphoria was associated with healthcare utilization measured by hospital cost per stay. Multivariate survey regression models were used to identify predictors., Results: Among the 1,892,760 total depression inpatient samples, 14,145 (0.7%) patients had gender dysphoria (per ICD-10 codes). Over the study periods, depression inpatients with gender dysphoria increased, but total depression inpatient rates remained stable. Survey regression results suggested that gender dysphoria, minority ethnicity or race, female sex assigned at birth, older ages, and specific hospital regions were associated with higher hospital cost per stay than their reference groups. Sub-group analysis showed that the trend was similar in most racial and regional groups., Conclusion: Differences in hospital cost per stay for depression inpatients with gender dysphoria exemplify how this community has been disproportionally affected by racial and regional biases, insurance denials, and economic disadvantages. Financial concerns can stop individuals from accessing gender-affirming care and risk more significant mental health problems. Increased complexity and comorbidity are associated with hospital cost per stay and add to the cycle., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kim, Medina, Park, Cho and Chang.)

The electronic sharing of health information holds the potential to enhance communication and coordination among hospitals and providers, ultimately leading to improved hospital performance. However, despite the benefits, hospitals often encounter significant challenges when it comes to sharing information with external parties. Our study aimed to identify the circumstances under which sharing information with external parties can result in changes in overall hospital costs, with a particular emphasis on various obstacles that hospitals may encounter, including lack of incentives or capabilities essential to facilitate effective information exchange. To achieve this goal, we obtain data from multiple sources, including the American Hospital Association (AHA) annual and IT surveys, the Center for Medicare and Medicaid Services (CMS) hospital compare dataset, and the Census Bureau's small-area income and poverty estimates. Consistent with previous research, we observed a significant reduction in hospital costs when information was shared internally but not externally. However, our findings also revealed that the sharing of health information can lead to cost savings for hospitals when they encounter challenges such as the absence of incentives and capabilities regardless of whether the information is shared internally or externally. The implication of our study is simple but strong: perseverance and effort yield positive outcomes. Only when hospitals push through challenges related to sharing information can they achieve the anticipated advantages of information sharing. Based on our results, we suggest that policymakers should strategically target hospitals and providers that face challenges in sharing health information rather than focusing on those without obstacles. This targeted approach can significantly increase policy efficiency, and we emphasize the need for policymakers to address the specific areas where hospitals and providers encounter difficulties. By doing so, they can effectively "scratch where it itches" and address the core issues hindering the successful exchange of health information.

Since ancient times, honey has been used in traditional medicine owing to its pharmacological effects. It possesses anticancer properties. However, the therapeutic implications of Sangju honey in cancer remains unknown. Therefore, we aimed to demonstrate the potential anticancer effects of Sangju honey on human oral squamous cell carcinoma (OSCC), particularly focusing on epithelial-mesenchymal transition (EMT) and apoptotic and mitogen-activated protein kinase (MAPK) signaling pathways. Ca9-22 and YD-10B human OSCC cells were treated with 0.25% or 0.5% Sangju honey, and the cell viability was examined using the Cell Counting Kit-8 assay. Cell morphology studies were conducted to observe morphological changes, and the wound-healing assay was performed to evaluate the proliferation of honey-treated OSCC cells. Western blot analysis was conducted to investigate protein expression related to EMT and apoptotic and MAPK signaling pathways. Sangju honey reduced cell viability, induced morphological changes, and significantly suppressed the proliferation and migration of Ca9-22 and YD-10B cells. The expression of E-cadherin and N-cadherin was increased and decreased, respectively, in both OSCC cell lines. Moreover, Sangju honey stimulated apoptosis by increasing the expression of p21, p53, cleaved caspase 3, and caspase 9. Furthermore, it downregulated the expression of phospho (p)-extracellular signal-regulated kinases 1 and 2, p-c-Jun amino-terminal kinase, and p-p38 in Ca9-22 and YD-10B cells. Sangju honey inhibits Ca9-22 and YD-10B cell proliferation by regulating EMT, inducing apoptosis, and suppressing the MAPK signaling pathway. Thus, it is a potential anticancer agent for human OSCC., Competing Interests: CONFLICTS OF INTEREST No potential conflicts of interest were disclosed., (Copyright © 2022 Korean Society of Cancer Prevention.)

6-Shogaol (SHO) and 6-gingerol (GIN), naturally derived compounds of ginger ( Zingiber officinale Roscoe), have been found to have anti-allergic effects on dermatitis-like skin lesions and rhinitis. Although SHO and GIN have demonstrated a potential in various inflammatory diseases, their efficacy and mechanism in asthma have not been largely examined. Therefore, the present study demonstrated the anti-asthmatic effects of SHO and GIN on the T-helper (Th) 2 cell-mediated allergic response pathway in an ovalbumin (OVA)-induced asthma mouse model. The asthma mouse model was established with an intraperitoneal (i.p.) injection of 50 µg OVA and 1 mg aluminum hydroxide with or without an i.p. injection of SHO and GIN (10 mg/kg) before treatment with OVA. In addition, the current study assessed mast cell degranulation in antigen-stimulated RBL-2H3 cells under different treatment conditions (SHO or GIN at 0, 10, 25, 50 and 100 nM) and determined the mRNA and protein levels of anti-oxidative enzymes [superoxide dismutase (SOD)1, SOD2, glutathione peroxidase-1/2, catalase] in lung tissues. SHO and GIN inhibited eosinophilia in the bronchoalveolar lavage fluids and H&E-stained lung tissues. Both factors also decreased mucus production in periodic acid-Schiff-stained lung tissues and the levels of Th2 cytokines in these tissues. GIN attenuated oxidative stress by upregulating the expression levels of anti-oxidative proteins. In an in vitro experiment, the degranulation of RBL-2H3 rat mast cells was significantly decreased. It was found that SHO and GIN effectively suppressed the allergic response in the mouse model by inhibiting eosinophilia and Th2 cytokine production. Collectively, it was suggested that SHO can inhibit lung inflammation by attenuating the Th2 cell-mediated allergic response signals, and that GIN can inhibit lung inflammation and epithelial cell remodeling by repressing oxidative stress. Therefore, SHO and GIN could be used therapeutically for allergic and eosinophilic asthma., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Kim et al.)

This study explores factors associated with the breadth (extent) and depth (level of detail) of digital information exchange among stakeholders in health information technology (IT) systems. Annual and IT surveys of the American Hospital Association and the U.S. Census Bureau's small-area income and poverty estimates from 2014-2016 were analyzed for associations between key factors and breadth and depth of information exchange. OLS Regression was used with a sample consisting of 10,040 year-hospital observations. We found that hospital-level variables such as size, ownership type, system affiliation, physician-hospital arrangement, and revenue model affect information exchange. We further found that market-level variables such as concentration ratio, urbanness, and median household income, although they directly affect information exchange, do not moderate the relationship between hospital-level variables and information exchange. Our study fills a gap in the previous literature arising from the lack of research on the determinants of health information exchange.

Despite substantial progress in the adoption of health information technology (IT), researchers remain uncertain as to whether IT investments benefit hospitals. This study evaluates the effect of health information sharing on the cost of care, and whether the effect varies with context. Our results suggest that information sharing using health IT, specifically the extent (breadth) and level of detail (depth) of information sharing, helps to reduce the cost of care at the hospital level. The results also show that the effects of depth of information sharing on cost savings are salient in poor and less-concentrated regions, but not in wealthier, more-concentrated areas, whereas the the effects of breadth of information sharing on cost savings are equivalent across wealth and concentration. To realize the benefits of using health IT more effectively, policy makers' strategies for encouraging active use of health IT should be informed by market characteristics.

Traumatic brain injury (TBI) is a well-established risk factor for several neurodegenerative disorders including Alzheimer's disease and Parkinson's disease, however, a link between TBI and amyotrophic lateral sclerosis (ALS) has not been clearly elucidated. Using the SOD1 G93A rat model known to recapitulate the human ALS condition, we found that exposure to mild, repetitive TBI lead ALS rats to experience earlier disease onset and shortened survival relative to their sham counterparts. Importantly, increased severity of early injury symptoms prior to the onset of ALS disease symptoms was linked to poor health of corticospinal motor neurons and predicted worsened outcome later in life. Whereas ALS rats with only mild behavioral injury deficits exhibited no observable changes in corticospinal motor neuron health and did not present with early onset or shortened survival, those with more severe injury-related deficits exhibited alterations in corticospinal motor neuron health and presented with significantly earlier onset and shortened lifespan. While these studies do not imply that TBI causes ALS, we provide experimental evidence that head injury is a risk factor for earlier disease onset in a genetically predisposed ALS population and is associated with poor health of corticospinal motor neurons.

Background: This study aims to contribute to the ongoing policy and scholarly debate on physician-hospital integration (INT) and health care cost by providing evidence for the role of physician boards in mitigating hospital expenditure associated with INT., Methods: We conducted our study of the relationship between INT, physician boards, and hospital expenditure using data on hospitals in California. We obtained data from the Centers for Medicare and Medicaid Services, American Hospital Association, and California Office of Statewide Health Planning and Development from 2002 to 2006. A hospital fixed-effect ordinary least square (OLS) regression analysis was used., Results: Hospital expenditure was higher in a hospital with an integrated arrangement (e.g., a hospital that adopted an integrated salary model) than under other independent arrangements between physicians and hospitals, and the proportion of physician members on hospital boards negatively moderated the effect of integration on hospital expenditure., Conclusions: Physician boards may provide a context that affords benefits that can reduce hospital expenditures under INT. This finding highlights the importance to having a supportive organizational design when implementing INT.

Executive Summary: This research was motivated by the large investment in health information technology (IT) by hospitals and the inconsistent findings related to the effects of health IT adoption on hospital performance. Building on resource orchestration theory and the information systems literature, the authors developed a research model to investigate how the configuration strategies for sharing information under health IT systems affect hospital efficiency. The hypotheses were tested using data from the 2010 annual and IT surveys of the American Hospital Association, Centers for Medicare & Medicaid Services case mix index, and U.S. Census Bureau's small-area income and poverty estimates. The study revealed that in health IT systems, the breadth (extent) and depth (level of detail) of digital information sharing among stakeholders each has a curvilinear relationship with hospital efficiency. In addition, breadth and depth reinforce each other's positive effects and attenuate each other's negative effects, and their balance has a positive effect on hospital efficiency. The results of this research have the potential to enrich the literature on the value of adopting health IT systems as well as in providing practitioner guidelines for meaningful use.

Background and Objectives: Despite the introduction of Medicare Part D (MPD) and 2012 Affordable Care Act (ACA), patients have a cost burden due to increases in drug prices. To overcome cost barriers, some patients purchase their medications from Canadian online pharmacies as Canadian prescription drug prices are believed to be lower than US prescription drug prices. The objective of this study was to determine which top 100 Medicare drugs can be imported to the USA legally, and to determine which type of prescription drug would be more beneficial to be purchased from Canadian online pharmacies. Moreover, we also deemed it important to compare MPD beneficiary annual expenses with expenses patients would have when obtaining their prescriptions from Canadian online pharmacies., Methods: We conducted a cost analysis from a patient perspective. A list of the top 100 Medicare drugs was compiled and information on drug prices was collected from three Canadian online pharmacies and four MPD plans in Virginia. The annual cost of each Medicare drug and percent change between Canadian online pharmacies and MPD were compared., Results: A total of 78 drugs from the top 100 Medicare drugs were included in the final analysis. Seventy-six prescription drugs (97.4%) that could be purchased from Canadian online pharmacies showed a significantly lower average drug price percent change of -72.71% (P < 0.0001). The heart health/blood pressure subgroup had the highest number of drugs that could be purchased from Canadian online pharmacies., Conclusion: The majority of prescription drugs can be purchased at lower prices from Canadian online pharmacies when compared to Medicare beneficiaries' potential expenses. Purchasing medications from Canadian online pharmacies may be a viable option to address cost barriers.

Unlabelled: Persistent infection of hepatitis C virus (HCV) is one of the leading causes of end-stage liver disease (ESLD), such as decompensated cirrhosis and liver cancer. Of particular note, nearly half of HCV-infected people in the United States are reported to be heavy drinkers. This particular group of patients is known to rapidly progress to the ESLD. Although accelerated disease progression among alcohol abusers infected with HCV is clinically well recognized, the molecular pathophysiology behind this manifestation has not been well elucidated. Hepatocytes metabolize ethanol (EtOH) primarily through two steps of oxidative catabolism in which alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) play central roles. The ADH-ALDH pathway also governs the metabolism of retinol (vitamin A) to its transcriptionally active metabolite, retinoic acid (RA). In this study, we defined that the ADH-ALDH pathway serves as a potent antiviral host factor in hepatocytes, which regulates the expression of interferon (IFN)-stimulated genes (ISGs) by biogenesis of RA. ISGs constitute over 300 antiviral effectors, which cooperatively govern intracellular antiviral innate immunity. Our study revealed that intracellular RA levels greatly influence ISG expression under basal conditions. Moreover, RA augments ISG induction in response to viral infection or exposure to IFN in a gene-specific manner. Lastly, our results demonstrated that EtOH attenuates the antiviral function of the ADH-ALDH pathway, which suggests the possibility that EtOH-retinol metabolic competition is one of the molecular mechanisms for the synergism between HCV and alcohol abuse in liver disease progression., Conclusions: RA plays a critical role in the regulation of intracellular antiviral innate immunity in hepatocytes. (Hepatology 2016;63:1783-1795)., (© 2015 by the American Association for the Study of Liver Diseases.)

Given that the enactment of the Patient Protection and Affordable Care Act of 2010 is expected to generate forces toward physician-hospital integration, this study examined an understudied, albeit important, area of costs incurred in physician-hospital integration. Such costs were analyzed through 24 semi-structured interviews with physicians and hospital administrators in a multiple-case, inductive study. Two extreme types of physician-hospital arrangements were examined: an employed model (ie, integrated salary model, a group of physicians integrated by a hospital system) and a private practice (ie, a physician or group of physicians who are independent of economic or policy control). Interviews noted that integration leads to 3 evident costs, namely, monitoring, coordination, and cooperation costs. Improving our understanding of the kinds of costs that are incurred after physician-hospital integration will help hospitals and physicians to avoid common failures after integration.

Objectives: To determine the impact of health information technology (HIT) adoption and hospital-physician integration on hospital efficiency., Study Design: Using 2010 data from the American Hospital Association's (AHA) annual survey, the AHA IT survey, supplemented by the CMS Case Mix Index, and the US Census Bureau's small area income and poverty estimates, we examined how the adoption of HIT and employment of physicians affected hospital efficiency and whether they were substitutes or complements., Methods: The sample included 2173 hospitals. We employed a 2-stage approach. In the first stage, data envelopment analysis was used to estimate technical efficiency of hospitals. In the second stage, we used instrumental variable approaches, notably 2-stage least squares and the generalized method of moments, to examine the effects of IT adoption and integration on hospital efficiency., Results: We found that HIT adoption and hospital-physician integration, when considered separately, each have statistically significant positive impacts on hospital efficiency. Also, we found that hospitals that adopted HIT with employed physicians will achieve less efficiency compared with hospitals that adopted HIT without employed physicians., Conclusions: Although HIT adoption and hospital-physician integration both seem to be key parts of improving hospital efficiency when one or the other is utilized individually, they can hurt hospital efficiency when utilized together.

In response to viral infection, the host induces over 300 IFN-stimulated genes (ISGs), which are the central component of intracellular antiviral innate immunity. Inefficient induction of ISGs contributes to poor control and persistence of hepatitis C virus infection. Therefore, further understanding of the hepatocytic ISG regulation machinery will guide us to an improved management strategy against hepatitis C virus infection. In this study, comprehensive genome-wide, high-throughput cDNA screening for genes regulating ISG expression identified a tyrosine kinase nonreceptor 1 (TNK1) as a unique player in the ISG induction pathway. The immune-modulatory function of TNK1 has never been studied, and this study characterizes its significance in antiviral innate immunity. TNK1 is abundantly expressed in hepatocytes and maintains basal ISG expression. More importantly, TNK1 plays a critical role in type I IFN-mediated ISG induction. We discovered that the activated IFN receptor complex recruits TNK1 from the cytoplasm. TNK1 is then phosphorylated to enhance its kinase activity. The activated TNK1 potentiates JAK-STAT signaling through dual phosphorylation of STAT1 at tyrosine 701 and serine 727 amino acid positions. Our loss-of-function approach demonstrated that TNK1 governs a cluster of ISG expression that defines the TNK1 pathway effector genes. More importantly, TNK1 abundance is inversely correlated to viral replication efficiency and is also a determinant factor for the hepatocytic response to antiviral treatment. Taken together, our studies found a critical but unidentified integrated component of the IFN-JAK-STAT signaling cascade.