Safety, tolerability and pharmacokinetics and pharmacodynamics of HL2351, a novel hybrid fc-fused interleukin-1 receptor antagonist, in healthy subjects: A first-in-human study.

AIMS: We performed a first-in-human study with HL2351, a novel hybrid Fc-fused interleukin (IL)-1 receptor antagonist, to evaluate its tolerability, pharmacokinetics and pharmacodynamics (PD) after a single subcutaneous (SC) administration in healthy subjects. METHODS: A randomized, double-blind, placebo- and active-controlled, dose-escalation study was conducted. Eligible subjects randomly received a single SC administration of HL2351 (1, 2, 4, 8 and 12 mg/kg) or placebo in a ratio of 8:2. Subjects in the active-controlled group received a single SC administration of anakinra at 100 mg. Serial blood samples were collected for pharmacokinetics and PD analyses. An ex-vivo activation test was performed to evaluate the PD using peripheral blood mononuclear cells treated with IL-1ß. Anti-HL2351 antibodies were determined at baseline and 29 days postdose. Tolerability was assessed throughout the study. RESULTS: HL2351 was eliminated more slowly than anakinra (terminal half-life: 27.21-45.28 vs 3.97 h). Serum concentrations of HL2351 were increased dose-proportionally. The mean apparent clearance of HL2351 were 0.6, 0.66, 0.75, 0.51, 0.65 L/h at 1, 2, 4, 8 and 12 mg/kg, respectively. The percent inhibition of IL-6 expression varied widely (range: 0-92.1%), showing no clear trend or discernible difference between HL2351, anakinra and placebo. HL2351 was well tolerated after a single SC administration. CONCLUSION: HL2351 was well tolerated and showed linear pharmacokinetic characteristics after a single SC administration at doses up to 12 mg/kg in healthy subjects. HL2351 remained in the body 7-11 times longer than anakinra. HL2351 can be developed as a potential therapeutic alternative to anakinra.

Calcitonin gene-related peptide regulation of glial cell-line derived neurotrophic factor in differentiated rat myotubes.

Glial cell-line derived neurotrophic factor (GDNF) is the most potent trophic factor for motoneuron survival and neuromuscular junction formation. GDNF is upregulated in injured or denervated skeletal muscle and returns to normal levels following reinnervation. However, the mechanism by which GDNF is regulated in denervated muscle is not well understood. The nerve-derived neurotransmitter calcitonin gene-related peptide (CGRP) is upregulated following neuromuscular injury and is subsequently released from motoneurons at the neuromuscular junction. CGRP also promotes nerve regeneration, but the mechanism is not well understood. The current study investigates whether this increase in CGRP regulates GDNF, thus playing a key role in promoting regeneration of injured nerves. This study demonstrates that CGRP increases GDNF secretion without affecting its transcription or translation. Rat L6 myoblasts were differentiated into myotubes and subsequently treated with CGRP. GDNF mRNA expression levels were quantified by quantitative real-time reverse transcription-polymerase chain reaction, and secreted GDNF was quantified in the conditioned medium by ELISA. CGRP treatment increased secreted GDNF protein without altering GDNF mRNA levels. The translational inhibitor cycloheximide did not affect CGRP-induced GDNF secreted protein levels, whereas the secretional inhibitor brefeldin A blocked the CGRP-induced increase in GDNF. This study highlights the importance of injury-induced upregulation of CGRP by exposing its ability to increase GDNF levels and demonstrates a secretional mechanism for regulation of this key regeneration-promoting neurotrophic factor.

Assessing health program performance in low- and middle-income countries: building a feasible, credible, and comprehensive framework.

BACKGROUND: Many health service delivery models are adapting health services to meet rising demand and evolving health burdens in low- and middle-income countries. While innovative private sector models provide potential benefits to health care delivery, the evidence base on the characteristics and impact of such approaches is limited. We have developed a performance measurement framework that provides credible (relevant aspects of performance), feasible (available data), and comparable (across different organizations) metrics that can be obtained for private health services organizations that operate in resource-constrained settings. METHODS: We synthesized existing frameworks to define credible measures. We then examined a purposive sample of 80 health organizations from the Center for Health Market Innovations (CHMI) database (healthmarketinnovations.org) to identify what the organizations reported about their programs (to determine feasibility of measurement) and what elements could be compared across the sample. RESULTS: The resulting measurement framework includes fourteen subgroups within three categories of health status, health access, and operations/delivery. CONCLUSIONS: The emphasis on credible, feasible, and comparable measures in the framework can assist funders, program managers, and researchers to support, manage, and evaluate the most promising strategies to improve access to effective health services. Although some of the criteria that the literature views as important - particularly population coverage, pro-poor targeting, and health outcomes - are less frequently reported, the overall comparison provides useful insights.

Increase in use of protective earplugs by Rock and Roll concert attendees when provided for free at concert venues.

OBJECTIVE: To determine the prevalence of hearing protection use among attendees of Rock and Roll concerts at baseline and in concerts where earplugs are provided for free at concert venue entrances. DESIGN: Six concerts performed at two music venues in Toronto, Canada were evaluated. Study personnel observed and recorded the use of hearing protection at three concerts where no earplugs were distributed, and three concerts where earplugs were provided for free at the concert venue entrance. STUDY SAMPLE: A total of 955 individuals over the age of 18 were observed at six concerts. Six hundred and thirty-seven individuals (64% male) were observed at concerts where no earplugs were provided, and 318 individuals (68% male) were observed at concerts where free earplugs were provided. RESULTS: Multivariate logistic regression demonstrated a significant increase in hearing protection usage at concerts where earplugs were provided for free at the concert venue entrance, odds ratio 7.27 (95% CI: 3.24-16.30). CONCLUSION: The provision of free earplugs at concert venues may be a simple and inexpensive intervention that could be a component of a larger public health campaign to prevent non-occupational noise-induced hearing loss.

Antipruritic effect of ursolic acid through MRGPRX2/MrgprB2-dependent inhibition of mast cell degranulation and reduced TSLP production.

Ursolic acid (UA), a pentacyclic triterpene, exhibits diverse pharmacological effects, including potential treatment for allergic diseases. It downregulates thymic stromal lymphopoietin (TSLP) and disrupts mast cell signaling pathways. However, the exact molecular mechanism of how UA interference with mast cell action remains unclear. Therefore, the current study aimed to uncover molecular entities underlying the effect of UA on mast cells and its potential antipruritic effect, specifically investigating its modulation of key molecules like TRPV4, PAR2, and MRGPRX2 involved in TSLP regulation and sensation. Calcium imaging experiments revealed that UA pretreatment significantly suppressed MRGPRX2 activation (and its mouse orthologue MrgprB2), a G protein-coupled receptor predominantly expressed in mast cells. Molecular docking predictions suggested potential interactions between UA and MRGPRX2/MrgprB2. UA pretreatment also reduced mast cell degranulation through MRGPRX2 and MrgprB2-dependent mechanisms. In a dry skin mouse model, UA administration decreased tryptase and TSLP production in the skin, and diminished TSLP response in the sensory neurons. While PAR2 and TRPV4 activation enhances TSLP production, UA did not inhibit their activity. Notably, UA attenuated compound 48/80-induced scratching behaviors in mice and suppressed spontaneous scratching in a dry skin model. The present study confirms the effective inhibition of UA on MRGPRX2/MrgprB2, leading to reduced mast cell degranulation and suppressed scratching behaviors. These findings highlight the potential of UA as an antipruritic agent for managing various allergy- or itch-related conditions.

The Factors Associated with Health Promotion Behavior of International Students in South Korea.

BACKGROUND: We aimed to explore the factors associated with health promotion behavior of international students in South Korea. METHODS: The convenience sample of 263 participants was recruited from two universities in Gangwon-do and Jeollanam-do, South Korea. The data were collected by using structured questionnaires from Apr to Jun 2019. Demographic characteristics, health conception, acculturative stress, self-efficacy, interpersonal support, and health promotion behavior were assessed. T-test, ANOVA, and multiple regression analyses were used for statistical analyses. RESULTS: Participants from Vietnam (P=.040), with more health conception (P<.001), more acculturative stress (P<.001), more self-efficacy (P<.001), and greater interpersonal support (P<.001) were more likely to engage in more health promotion behaviors. CONCLUSION: This study is meaningful as it collected the data on which to design health promotion programs for international students. Future studies are needed to investigate further factors relating to international students' health promotion behavior, including internal and external environments.

Health-Related Quality of Life Based on Comorbidities Among Patients with End-Stage Renal Disease.

OBJECTIVES: The aim of this study was to investigate comorbidities in patients with end-stage renal disease, and to compare health-related quality of life (HRQOL) according to the type, and number of comorbidities. METHODS: A total of 250 adults undergoing hemodialysis were recruited at local clinics. HRQOL was measured using the 12-item Medical Outcomes Study Short Form questionnaire. Data were analyzed using descriptive statistics, analysis of variance, and t test. RESULTS: Around 70.8% of patients with end stage renal disease had 1 or more comorbidities, and the most common comorbidities were hypertension, diabetes, and cardiovascular disease. HRQOL was significantly different based on the number of comorbidities (F = 9.83, p < 0.001). The effect of comorbidities on the scores for mental health domains of the HRQOL questionnaire was not conclusive compared with the scores for the physical domain which were conclusive. Among the comorbidities, diabetes was associated with a lower quality of life. CONCLUSION: The customized management of diabetic and hypertensive patients is necessary for the early detection and prevention of chronic kidney disease, and slowing the progression of renal disease and managing cardiovascular risk factors is essential.

Access to surgery following centralization of breast cancer surgical consultations.

INTRODUCTION: Timely access to breast cancer surgery is imperative for patient outcome. Building upon our previous model, 5 breast surgeons centralized all breast surgical referrals using principles of centralized intake and nurse navigator triage. The goal of this study was to investigate whether centralization can further improve access to surgery. METHODS: This study was designed as a before-after series, comparing wait times for breast cancer surgery prior to centralization and after. Primary outcome was wait time from diagnosis to surgery, and secondary outcomes included median wait time, days required for 90% case completion, number of available operating days, and number of patients who underwent breast reconstruction and neoadjuvant therapy. RESULTS: Overall, centralization of breast cancer surgical referrals reduced wait time from 47 to 41 days. The median wait time and time required for 90% of case completion was reduced, despite a 7% reduction in operating room availability. Fewer patients underwent neoadjuvant therapy and more patients underwent breast reconstruction following centralization. CONCLUSION: Centralization of surgical referrals for breast cancer patients improved access to surgery.

[Structural Equation Modeling of Self-Management in Patients with Hemodialysis].

PURPOSE: The purpose of this study was to construct and test a hypothetical model of self-management in patients with hemodialysis based on the Self-Regulation Model and resource-coping perspective. METHODS: Data were collected from 215 adults receiving hemodialysis in 17 local clinics and one tertiary hospital in 2016. The Hemodialysis Self-management Instrument, the Revised Illness Perception Questionnaire, Herth Hope Index and Multidimensional Scale of Perceived Social Support were used. The exogenous variable was social context; the endogenous variables were cognitive illness representation, hope, self-management behavior, and illness outcome. For data analysis, descriptive statistics, Pearson correlation analysis, factor analysis, and structural equation modeling were performed. RESULTS: The hypothetical model with six paths showed a good fitness to the empirical data: GFI=.96, AGFI=.90, CFI=.95, RMSEA=.08, SRMR=.04. The factors that had an influence on self-management behavior were social context (ß=.84), hope and cognitive illness representation (ß=.37 and ß=.27) explaining 92.4% of the variance. Self-management behavior mediated the relationship between psychosocial coping resources and illness outcome. CONCLUSION: This research specifies a more complete spectrum of the self-management process. It is important to recognize the array of clinical resources available to support patients' self-management. Healthcare providers can facilitate self-management through collaborative care and understanding the ideas and emotions that each patient has about the illness, and ultimately improve the health outcomes. This framework can be used to guide self-management intervention development and assure effective clinical assessment.

Restrictive use of perioperative blood transfusion does not increase complication rates in microvascular breast reconstruction.

INTRODUCTION: With increasing appreciation of the possible adverse effects of peri-operative blood transfusion, restrictive policies regarding use of blood products have been adopted in many surgical specialties. Although microvascular breast reconstruction has become a routine procedure, high peri-operative transfusion rates continue to be reported in the literature. In this study we examine the impact of our restrictive approach on blood transfusion rates and postoperative complications in patients undergoing microvascular blood transfusion. METHODS: A retrospective review of patients undergoing microvascular breast reconstruction with abdominal flaps at a single institution was performed. Patient age and body mass index as well as type, timing and laterality of reconstruction was recorded. Pre-operative and post-operative hemoglobin and hematocrit were recorded. Peri-operative blood transfusion rates were calculated. Post-operative complication rates were compared between patients with higher and lower post-operative hemoglobin levels. RESULTS: Five hundred and twelve patients were included in this study. The peri-operative transfusion rate was 0.98% in this series. There was no significant difference between transfusion rates in unilateral and bilateral reconstructions (0.68 vs 1.36% p = 0.08) or immediate and delayed reconstructions (1.02 vs 0.51% p = 0.72 and 1.01 vs 1.60% p = 0.09 for unilateral and bilateral respectively). Lower post-operative hemoglobin levels were not associated with increased flap related, surgical or medical complications rates. CONCLUSION: A restrictive approach to peri-operative blood transfusion can be safely adopted in microvascular breast reconstruction without compromising flap viability or overall complication rates.

Architecture Design of Healthcare Software-as-a-Service Platform for Cloud-Based Clinical Decision Support Service.

OBJECTIVES: To design a cloud computing-based Healthcare Software-as-a-Service (SaaS) Platform (HSP) for delivering healthcare information services with low cost, high clinical value, and high usability. METHODS: We analyzed the architecture requirements of an HSP, including the interface, business services, cloud SaaS, quality attributes, privacy and security, and multi-lingual capacity. For cloud-based SaaS services, we focused on Clinical Decision Service (CDS) content services, basic functional services, and mobile services. Microsoft's Azure cloud computing for Infrastructure-as-a-Service (IaaS) and Platform-as-a-Service (PaaS) was used. RESULTS: The functional and software views of an HSP were designed in a layered architecture. External systems can be interfaced with the HSP using SOAP and REST/JSON. The multi-tenancy model of the HSP was designed as a shared database, with a separate schema for each tenant through a single application, although healthcare data can be physically located on a cloud or in a hospital, depending on regulations. The CDS services were categorized into rule-based services for medications, alert registration services, and knowledge services. CONCLUSIONS: We expect that cloud-based HSPs will allow small and mid-sized hospitals, in addition to large-sized hospitals, to adopt information infrastructures and health information technology with low system operation and maintenance costs.

A novel small molecule HSP90 inhibitor, NXD30001, differentially induces heat shock proteins in nervous tissue in culture and in vivo.

Heat shock proteins (HSPs) are attractive therapeutic targets for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), characterized by aberrant formation of protein aggregates. Although motor neurons have a high threshold for activation of HSP genes, HSP90 inhibitors are effective inducers. This study evaluated NXD30001, a novel, small molecule HSP90 inhibitor based on the radicicol backbone, for its ability to induce neuronal HSPs and for efficacy in an experimental model of ALS based on mutations in superoxide-dismutase 1 (SOD1). In motor neurons of dissociated murine spinal cord cultures, NXD30001-induced expression of HSP70/HSPA1 (iHSP70) and its co-chaperone HSP40/DNAJ through activation of HSF1 and exhibited a protective profile against SOD1(G93A) similar to geldanamycin, but with less toxicity. Treatment prevented protein aggregation, mitochondrial fragmentation, and motor neuron death, important features of mutant SOD1 toxicity, but did not effectively prevent aberrant intracellular Ca(2+) accumulation. NXD30001 distributed to brain and spinal cord of wild-type and SOD1(G93A) transgenic mice following intraperitoneal injection; however, unlike in culture, in vivo levels of SOD1 were not reduced. NXD30001-induced expression of iHSP70 in skeletal and cardiac muscle and, to a lesser extent, in kidney, but not in liver, spinal cord, or brain, with either single or repeated administration. NXD30001 is a very useful experimental tool in culture, but these data point to the complex nature of HSP gene regulation in vivo and the necessity for early evaluation of the efficacy of novel HSP inducers in target tissues in vivo.

Multiple mutations of the critical amino acid residues for the sweetness of the sweet-tasting protein, brazzein.

We have previously identified critical residues important for sweetness of the sweet protein brazzein by site-directed mutagenesis (Yoon, Kong, Jo, & Kong, 2011). In order to elucidate the interaction mechanisms of brazzein with the sweet taste receptor, we made multiple mutations of three residues (His31 in loop 30-33, Glu36 in ß-strand III, and Glu41 in loop 40-43). We found that all double mutations (H31R/E36D, H31R/E41A and E36D/E41A) made the molecules sweeter than des-pE1M-brazzein and three single mutants. Moreover, the triple mutation (H31R/E36D/E41A) made the molecule significantly sweeter than three double mutants. These results strongly support the hypothesis that brazzein binds to the multisite surface of the sweet taste receptor. Our findings also suggest that mutations reducing the overall negative charge and/or increasing the positive charge favour sweet-tasting protein potency.