In vivo safety evaluation method for nanomaterials for cancer therapy.

Nanomaterials are extensively used in the diagnosis and treatment of cancer and other diseases because of their distinctive physicochemical properties, including the small size and ease of modification. The approval of numerous nanomaterials for clinical treatment has led to a significant increase in human exposure to these materials. When nanomaterials enter organisms, they interact with DNA, cells, tissues, and organs, potentially causing various adverse effects, such as genotoxicity, reproductive toxicity, immunotoxicity, and damage to tissues and organs. Therefore, it is crucial to elucidate the side effects and toxicity mechanisms of nanomaterials thoroughly before their clinical applications. Although methods for in vitro safety evaluation of nanomaterials are well established, systematic methods for in vivo safety evaluation are still lacking. This review focuses on the in vivo safety evaluation of nanomaterials and explores their potential effects. In addition, the experimental methods for assessing such effects in various disciplines, including toxicology, pharmacology, physiopathology, immunology, and bioinformatics are also discussed.

Impact of GnRH agonist and GnRH antagonist on GDF9 and BMP15 expression in mouse ovaries and oocyte development.

GnRH analogues were widely used for controlld ovary stimulation, but their effects on oocyte quality remain contradictory. This study aimed to explore the influence of GnRH analogues on oocyte quality in mice. A total of 120 mice were randomly assigned to four groups:(i)GnRH-a+PMSG group; (ii) GnRH-ant+PMSG group; (iii) PMSG group; (iv) Control group. Ovaries were collected for quantitative real-time polymerase chain reaction (qRT-PCR) to assess GDF9 and BMP15 mRNA expression, and protein expression were evaluated by western blotting. Moreover, embryo developmental progress in vitro and implantation rate in vivo were recorded. Compared with control group, both GDF9 mRNA and protein expressions were strengthened in PMSG group, but reduced in the presence of GnRH-a or GnRH-ant. The GnRH-a group exhibited decreased BMP15 mRNA expression compared to PMSG group, while the GnRH-ant group did not show the same pattern. BMP15 protein expression were not statisticlly different among the four groups. Notably, there was no statistically difference in the expression of these two factors between GnRH-a and GnRH-ant groups. The percentage of zygotes progressing to the 2-cell stage and percentage of 2-cell advancing to the blastocyst stage were similar in the PMSG group and control group. However, both the GnRH-a and GnRH-ant groups showed decreased embryos development rates compared to other two groups. The embryonic implantation rate in control group (53.3%) was higher than that in the GnRH-a and GnRH-ant groups (33.3% and 30.8%, P<0.05). The difference between the PMSG (45.0%) and GnRHa group was statistically significant (P value of 0.023), but not between the PMSG and GnRH-ant group (P value of 0.486). No statistical difference was confirmed between GnRH-a and GnRH-ant groups. Our findings shed light on the safety of GnRH analogues in ovary stimulation, and highlight the need for further research to establish optimal and effective controlled ovary stimulation protocol.

Evaluation of the relationship between endolymphatic hydrops and hearing loss in Meniere's disease based on three-dimensional real inversion recovery sequence

Abstract Objectives: The degree of endolymphatic hydrops in Meniere's disease may be related to hearing loss. However, the results of prior studies have been inconsistent. We aimed to investigate the relationship between endolymphatic hydrops and hearing loss characteristics in Meniere's disease. Methods: This study included 54 patients (62 ears) with Meniere's disease. Patients underwent three-dimensional real inversion recovery sequences for magnetic resonance imaging and puretone audiometry. Endolymphatic hydrops were assessed according to Gurkov's criteria (2011). Correlations between different degrees of endolymphatic hydrops and pure-tone audiometry, as well as staging, were analysed. Results: Pure tone audiometry and staging were higher for vestibular endolymphatic hydrops complicated by cochlear ones than isolated cochlear or vestibular hydrops (both p<0.05). There was no significant correlation between vestibular endolymphatic hydrops and pure-tonal audiometry or staging (all p > 0.05). The degree of hydrops in the middle turn was correlated with the mid-frequency hearing threshold (p<0.05). The degree of cochlear hydrops was correlated with the audiometry, low-frequency hearing thresholds, mid-frequency hearing thresholds and staging (p<0.01). Conclusion: The types and sites of endolymphatic hydrops based on a 3D-real inversion recovery sequence can be used to indicate the degree of hearing loss in patients with Meniere's disease. Level of evidence: Level III.

Evaluation of the relationship between endolymphatic hydrops and hearing loss in Meniere's disease based on three-dimensional real inversion recovery sequence.

OBJECTIVES: The degree of endolymphatic hydrops in Meniere's disease may be related to hearing loss. However, the results of prior studies have been inconsistent. We aimed to investigate the relationship between endolymphatic hydrops and hearing loss characteristics in Meniere's disease. METHODS: This study included 54 patients (62 ears) with Meniere's disease. Patients underwent three-dimensional real inversion recovery sequences for magnetic resonance imaging and pure-tone audiometry. Endolymphatic hydrops were assessed according to Gurkov's criteria (2011). Correlations between different degrees of endolymphatic hydrops and pure-tone audiometry, as well as staging, were analysed. RESULTS: Pure tone audiometry and staging were higher for vestibular endolymphatic hydrops complicated by cochlear ones than isolated cochlear or vestibular hydrops (both p < 0.05). There was no significant correlation between vestibular endolymphatic hydrops and pure-tonal audiometry or staging (all p > 0.05). The degree of hydrops in the middle turn was correlated with the mid-frequency hearing threshold (p < 0.05). The degree of cochlear hydrops was correlated with the audiometry, low-frequency hearing thresholds, mid-frequency hearing thresholds and staging (p < 0.01). CONCLUSION: The types and sites of endolymphatic hydrops based on a 3D-real inversion recovery sequence can be used to indicate the degree of hearing loss in patients with Meniere's disease. LEVEL OF EVIDENCE: Level III.

Severe anemia is associated with increased short-term and long-term mortality in patients hospitalized with cirrhosis.

INTRODUCTION AND OBJECTIVES: The relationship between anemia and the outcome of patients with cirrhosis is not completely clear. Therefore, we performed this large-scale epidemiological study to investigate the prevalence and severity of anemia in patients with cirrhosis and acute decompensation or liver injury and how anemia impacts short-term and long-term outcomes. PATIENTS AND METHODS: Patients with cirrhosis and acute decompensation (AD) or acute liver injury (ALI) were enrolled in the Chinese AcuTe on CHronic LIver FailurE (CATCH-LIFE) studies, which consisted of two large, multicenter, prospective, observational cohorts between January 2015 and December 2016 and July 2018 and January 2019. We conducted data analysis on the prevalence of anemia and determined the relationship between anemia and prognosis. RESULTS: Among 1979 patients, 1389 (70.2%) had anemia, among whom 599 (41.3%) had mild anemia, 595 (15.8%) had moderate anemia and 195 (2.4%) had severe anemia. A linear association between hemoglobin level and 90-day or 1-year LT-free mortality was shown, and a 10 g/L decrease in hemoglobin level was associated with a 6.8% extra risk of 90-day death and a 5.7% extra risk of 1-year death. Severe anemia was an independent risk factor for 90-day [HR=1.649 (1.100, 2.473), p=0.016] and 1-year LT-free mortality [HR=1.610 (1.159, 2.238), p=0.005]. Multinomial logistic regression analysis further identified that severe anemia was significantly associated with post-28-day mortality but not within-28-day mortality. CONCLUSIONS: Anemia is common in patients with cirrhosis admitted for acute events. Severe anemia was associated with poor 90-day and 1-year prognoses in these patients.

Downregulated miR-181a alleviates H2O2-induced oxidative stress and cellular senescence by targeting PDIA6 in human foreskin fibroblasts

Abstract Background Oxidative stress is strongly associated with cellular senescence. Numerous studies have indicated that microRNAs (miRNAs) play a critical part in cellular senescence. MiR-181a was reported to induce cellular senescence, however, the potential mechanism of miR-181a in hydrogen peroxide (H2O2)-induced cellular senescence remains obscure. Objective The aim of this study is to investigate the role and regulatory mechanism of miR-181a in H2O2-induced cellular senescence. Methods Human foreskin fibroblasts (HFF) transfected with miR-181a inhibitor/miR-NC with or without H2O2 treatment were divided into four groups: control + miR-NC/miR-181a inhibitor, H2O2 + miR-NC/miR-181a inhibitor. CCK-8 assay was utilized to evaluate the viability of HFF. RT-qPCR was used to measure the expression of miR-181a and its target genes. Protein levels of protein disulfide isomerase family A member 6 (PDIA6) and senescence markers were assessed by western blotting. Senescence-associated β-galactosidase (SA-β-gal) staining was applied for detecting SA-β-gal activity. The activities of SOD, GPx, and CAT were detected by corresponding assay kits. The binding relation between PDIA6 and miR-181a was identified by luciferase reporter assay. Results MiR-181a inhibition suppressed H2O2-induced oxidative stress and cellular senescence in HFF. PDIA6 was targeted by miR-181a and lowly expressed in H2O2-treated HFF. Knocking down PDIA6 reversed miR-181a inhibition-mediated suppressive impact on H2O2-induced oxidative stress and cellular senescence in HFF. Study limitations Signaling pathways that might be mediated by miR-181a/PDIA6 axis were not investigated. Conclusion Downregulated miR-181a attenuates H2O2-induced oxidative stress and cellular senescence in HFF by targeting PDIA6.

Real-world impact of empagliflozin on total cost of care in adults with type 2 diabetes: Results from an outcomes-based agreement.

BACKGROUND: Value-based health care is expanding through payment models such as outcomes-based agreements between manufacturers and payers. OBJECTIVE: To describe the total-cost-of-care outcomes of an outcomes-based agreement evaluating the real-world impact of empagliflozin vs other type 2 diabetes mellitus (T2DM) drugs among all patients with T2DM, with and without cardiovascular disease (within and beyond the requirement of the agreement). METHODS: In this prospective real-world analysis, members from the health plan of an integrated health care delivery system from the commercial and Medicare Advantage lines of business, who qualify under the confines of the contract, were included for analysis. Thus, members aged 18 years and older who were continuously enrolled in the identification (January 1, 2018, to December 31, 2018) and measurement periods (≤1 year post-index) with a T2DM diagnosis were retained. Patients using empagliflozin and empagliflozin-combination drugs constituted the empagliflozin group; those using all other antihyperglycemics, the nonempagliflozin group. Patients with type 1 diabetes, or those using metformin or insulin monotherapy, at index were excluded. Eligible members were followed for up to the earliest occurrence of disenrollment date, discontinuation (60-day medication fill gap allowed) of empagliflozin (or nonempagliflozin containing) medication, or the end of the measurement period. We compared, using Student's t-test and summary statistics (for reporting the outcomes agreement) and a propensity-matched difference-in-difference model (for the followup evaluation beyond the requirement of the agreement), the mean all-cause total cost of care (pharmacy plus medical) per patient per month (PPPM) between the 2 groups, including a subgroup of members with a baseline cardiovascular disease diagnosis. RESULTS: There were 4,577 (3,069 and 1,508 in the commercial and Medicare) and 33,712 (15,571 and 18,141 in the commercial and Medicare) in the empagliflozin and nonempagliflozin groups, respectively. The difference in mean total cost PPPM was $75 lower for empagliflozin vs nonempagliflozin groups, driven mainly by lower medical costs in the empagliflozin group (-$465 PPPM). However, the difference was not statistically significant in the propensity score-matched model. CONCLUSIONS: Although empagliflozin had higher pharmacy costs, the total cost of care for patients with T2DM and with established cardiovascular disease were comparable to the group of patients with all other T2DM, driven mainly by lower medical costs. DISCLOSURES: The authors report no conflicts of interest beyond being employees of the 2 organizations involved in this outcomes-based agreement. Ms. Palli is a former employee of Boehringer Ingelheim Pharmaceuticals, Inc., who was affiliated at the time of study conduct.

Downregulated miR-181a alleviates H2O2-induced oxidative stress and cellular senescence by targeting PDIA6 in human foreskin fibroblasts.

BACKGROUND: Oxidative stress is strongly associated with cellular senescence. Numerous studies have indicated that microRNAs (miRNAs) play a critical part in cellular senescence. MiR-181a was reported to induce cellular senescence, however, the potential mechanism of miR-181a in hydrogen peroxide (H2O2)-induced cellular senescence remains obscure. OBJECTIVE: The aim of this study is to investigate the role and regulatory mechanism of miR-181a in H2O2-induced cellular senescence. METHODS: Human foreskin fibroblasts (HFF) transfected with miR-181a inhibitor/miR-NC with or without H2O2 treatment were divided into four groups: control + miR-NC/miR-181a inhibitor, H2O2 + miR-NC/miR-181a inhibitor. CCK-8 assay was utilized to evaluate the viability of HFF. RT-qPCR was used to measure the expression of miR-181a and its target genes. Protein levels of protein disulfide isomerase family A member 6 (PDIA6) and senescence markers were assessed by western blotting. Senescence-associated ß-galactosidase (SA-ß-gal) staining was applied for detecting SA-ß-gal activity. The activities of SOD, GPx, and CAT were detected by corresponding assay kits. The binding relation between PDIA6 and miR-181a was identified by luciferase reporter assay. RESULTS: MiR-181a inhibition suppressed H2O2-induced oxidative stress and cellular senescence in HFF. PDIA6 was targeted by miR-181a and lowly expressed in H2O2-treated HFF. Knocking down PDIA6 reversed miR-181a inhibition-mediated suppressive impact on H2O2-induced oxidative stress and cellular senescence in HFF. STUDY LIMITATIONS: Signaling pathways that might be mediated by miR-181a/PDIA6 axis were not investigated. CONCLUSION: Downregulated miR-181a attenuates H2O2-induced oxidative stress and cellular senescence in HFF by targeting PDIA6.

Using the health belief model to analyze nurses' perception toward their behaviors for keeping surgical instruments moist: a cross-sectional study.

BACKGROUND: Nurses' perception toward their behaviors for keeping surgical instruments moist has been rarely studied. METHODS: The survey which utilized a questionnaire regarding respondent's demographic information and a self-designed nurses' perception-behavior scale for keeping surgical instruments moist was conducted with 360 nurses from a hospital in China. RESULTS: Total score of nurses' perception-behavior scale for keeping surgical instruments moist was 139.93 ± 15.145. Score of nurses' perception-behavior scale for keeping surgical instruments moist varied with age, length of service, and job title, with a statistically significant difference (p < 0.05). Length of service was the main factor affecting nurses' perception toward their behaviors for keeping surgical instruments moist. CONCLUSIONS: Nurses should be offered intensive training on keeping surgical instruments moist due to their inadequate perception on it. The nurses' change in health beliefs and behaviors must be based on developing the right attitude.

OBJETIVO: La percepción de los enfermeros sobre sus comportamientos para mantener húmedo el instrumental quirúrgico ha sido poco estudiada. MÉTODOS: La encuesta que utilizó un cuestionario sobre la información demográfica del encuestado y una escala de percepción y comportamiento de las enfermeras de diseño propio para mantener húmedos los instrumentos quirúrgicos se realizó con 360 enfermeras de un hospital en China. RESULTADOS: La puntuación total de la escala de percepción-conducta de las enfermeras para mantener húmedo el instrumental quirúrgico fue de 139.93 ± 15.145. La puntuación de la escala de percepción-conducta de las enfermeras para mantener húmedos los instrumentos quirúrgicos varió con la edad, la duración del servicio y el cargo, con una diferencia estadísticamente significativa (p < 0,05). El tiempo de servicio fue el principal factor que influyó en la percepción de los enfermeros sobre sus comportamientos para mantener húmedo el instrumental quirúrgico. CONCLUSIÓN: Se debe ofrecer a las enfermeras un entrenamiento intensivo sobre el mantenimiento de la humedad del instrumental quirúrgico por su inadecuada percepción al respecto. El cambio de creencias y comportamientos de salud de las enfermeras debe basarse en el desarrollo de la actitud correcta.

Aß promotes CD38 expression in senescent microglia in Alzheimer's disease.

BACKGROUND: In Alzheimer's disease (AD), the neuroinflammatory response mediated by the activation of senescent microglia is closely related to energy dysmetabolism. However, the mechanism underlying the interaction between the energy metabolism of aging microglia and neuroinflammation remains unclear. METHODS: We used biochemical methods, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and western blot to determine the effects and mechanism of CD38 knockdown on energy metabolism and neuroinflammation in Aß1-40 injured BV2 cells. Using AD model mice, we detected CD38 enzyme activity, energy metabolism factors (ATP, NAD +, and NAD + /NADH), and neuroinflammatory factors (IL-1ß, IL-6, and TNF-α) following the addition of CD38 inhibitor. Using a combination of biochemical analysis and behavioral testing, we analyzed the effects of the CD38 inhibitor on energy metabolism disorder, the neuroinflammatory response, and the cognition of AD mice. RESULTS: Following Aß1-40 injury, SA-ß-Gal positive cells and senescence-related proteins P16 and P21 increased in BV2 cells, while energy-related molecules (ATP, NAD +, and NAD + /NADH) and mitochondrial function (mitochondrial ROS and MMP) decreased. Further studies showed that CD38 knockdown could improve Aß1-40-induced BV2 cells energy dysmetabolism and reduce the levels of IL-1ß, IL-6, and TNF-α. In vivo results showed an increase in senile plaque deposition and microglial activation in the hippocampus and cortex of 34-week-old APP/PS1 mice. Following treatment with the CD38 inhibitor, senile plaque deposition decreased, the number of Iba1 + BV2 cells increased, the energy metabolism disorder was improved, the proinflammatory cytokines were reduced, and the spatial learning ability was improved. CONCLUSIONS: Our results confirm that senescent microglia appeared in the brain of 34-week-old APP/PS1 mice, and that Aß1-40 can induce senescence of BV2 cells. The expression of CD38 increases in senescent BV2 cells, resulting in energy metabolism disorder. Therefore, reducing CD38 expression can effectively improve energy metabolism disorder and reduce proinflammatory cytokines. Following intervention with the CD38 inhibitor in APP/PS1 mice, the energy metabolism disorder was improved in the hippocampus and cortex, the level of proinflammatory cytokines was reduced, and cognitive impairment was improved.

Aß promotes CD38 expression in senescent microglia in Alzheimer's disease

BACKGROUND: In Alzheimer's disease (AD), the neuroinflammatory response mediated by the activation of senescent microglia is closely related to energy dysmetabolism. However, the mechanism underlying the interaction between the energy metabolism of aging microglia and neuroinflammation remains unclear. METHODS: We used biochemical methods, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and western blot to determine the effects and mechanism of CD38 knockdown on energy metabolism and neuroinflammation in Aß1-40 injured BV2 cells. Using AD model mice, we detected CD38 enzyme activity, energy metabolism factors (ATP, NAD +, and NAD +/NADH), and neuroinflammatory factors (IL-1ß, IL-6, and TNF-α) following the addition of CD38 inhibitor. Using a combination of biochemical analysis and behavioral testing, we analyzed the effects of the CD38 inhibitor on energy metabolism disorder, the neuroinflammatory response, and the cognition of AD mice. RESULTS: Following Aß1-40 injury, SA-ß-Gal positive cells and senescence-related proteins P16 and P21 increased in BV2 cells, while energy-related molecules (ATP, NAD +, and NAD +/NADH) and mitochondrial function (mitochondrial ROS and MMP) decreased. Further studies showed that CD38 knockdown could improve Aß1-40-induced BV2 cells energy dysmetabolism and reduce the levels of IL-1ß, IL-6, and TNF-α. In vivo results showed an increase in senile plaque deposition and microglial activation in the hippocampus and cortex of 34-week-old APP/PS1 mice. Following treatment with the CD38 inhibitor, senile plaque deposition decreased, the number of Iba1 +BV2 cells increased, the energy metabolism disorder was improved, the proinflammatory cytokines were reduced, and the spatial learning ability was improved. CONCLUSIONS: Our results confirm that senescent microglia appeared in the brain of 34-week-old APP/PS1 mice, and that Aß1-40 can induce senescence of BV2 cells. The expression of CD38 increases in senescent BV2 cells, resulting in energy metabolism disorder. Therefore, reducing CD38 expression can effectively improve energy metabolism disorder and reduce proinflammatory cytokines. Following intervention with the CD38 inhibitor in APP/PS1 mice, the energy metabolism disorder was improved in the hippocampus and cortex, the level of proinflammatory cytokines was reduced, and cognitive impairment was improved.

Acquirement of HRP conjunct IgG anti-IgMs from most widely cultured freshwater fishes in China and its immunoreactivity.

Until now, custom-made or commercial polyclonal antibody against only one kind of fish IgM limited application of the antibody. During our research on development of vaccine against infection of Clonorchis sinensis (C. sinensis) in several kinds of fish, we were conscious of the urgency of secondary antibody to evaluate immune effect and screen C. sinensis infection with immunological technology instead of labor-intensive and time-consuming squash or artificial digestion of fish flesh. So that, we purified IgM of grass carp, bighead carp, crucian carp, common carp and tilapia which were widely cultured freshwater fishes in most areas of China. On this basis, we generated HRP-conjunct rabbit IgG anti-fish IgMs with high titers. IgM of other freshwater fishes including oshima, yellow catfish, bream, silver carp and so on could be recognized by the IgG sensitively. Additionally, The ELISA detection displayed that the IgG could be more specific and sensitive than custom-made rabbit IgG anti-grass carp IgM. The acquirement of HRP-conjunct rabbit IgG anti-fish IgMs was the cornerstone for studying the immune system of teleost fish, developing immunoassay methods and evaluation of fish vaccine with more convenience.

Efficacy and safety of tolperisone versus baclofen among Chinese patients with spasticity associated with spinal cord injury: a non-randomized retrospective study.

There are many medications available to treat spasticity, but the tolerability of medications is the main issue for choosing the best treatment. The objectives of this study were to compare the efficacy and adverse effects of tolperisone compared to baclofen among patients with spasticity associated with spinal cord injury. Patients received baclofen plus physical therapy (BAF+PT, n=135) or tolperisone plus physical therapy (TOL+PT, n=116), or physical therapy alone (PT, n=180). The modified Ashworth scale score, the modified Medical Research Council score, the Barthel Index score, and the Disability Assessment scale score were improved (P<0.05 for all) in all the patients at the end of 6 weeks compared to before interventions. After 6 weeks, the overall coefficient of efficacy of the intervention(s) in the BAF+PT, TOL+PT, and PT groups were 1.15, 0.45, and 0.05, respectively. The patients of the BAF+PT group reported asthenia, drowsiness, and sleepiness and those of the TOL+PT group reported dyspepsia and epigastric pain as adverse effects. When comparing drug interventions to physical therapy alone, both baclofen plus physical therapy and tolperisone plus physical therapy played a significant role in the improvement of daily activities of patients. Nonetheless, baclofen plus physical therapy was tentatively effective. Tolperisone plus physical therapy was slightly effective. In addition, baclofen caused adverse effects related to the sedative manifestation (Level of Evidence: III; Technical Efficacy Stage: 4).

Changes in Type 2 Diabetes Medication Utilization and Costs in the United States, 2014-2019.

OBJECTIVE: The objective of this study was to describe national changes in utilization and associated costs of antidiabetic medications in the United States from 2014 to 2019, across different drug classes and insurance plans. RESEARCH DESIGN AND METHODS: This retrospective, cross-sectional study examined administrative claims from a large national pharmacy benefits manager from January 1, 2014, to December 31, 2019. Patients aged 18 years and above enrolled in commercial, Medicare, or Medicaid health plans who filled ≥1 prescription claim for an antidiabetic medication(s) during the 6-year period were included. Utilization was examined as the total number of 30-day adjusted prescription fills per user per month (PUPM). Gross costs were calculated as the sum of plan costs (net of rebates) and member out-of-pocket costs. Differences in mean utilization and costs PUPM between 2014 and 2019 for each medication class were calculated. RESULTS: The final analytic sample increased from 745,290 patients in 2014 to 1,596,006 in 2019. Antidiabetic medication utilization increased by 8.8% from 2014 to 2019, driven by increases in sodium-glucose cotransporter 2 inhibitor (48.7%; P<0.001), glucagon-like peptide 1 receptor agonist (11.8%; P<0.001), insulin (8.1%; P<0.001), and metformin (2.9%; P<0.05) utilization. Average costs PUPM rose 47.5% (P<0.001), from $126.52 in 2014 to $186.58 in 2019. Sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and combination drugs contributed significantly to these increased costs, with 6-year cost differences of 57.3%, 46.9%, and 47.2%, respectively (all P<0.001). CONCLUSION: Our study demonstrates a shift in antidiabetic medication class utilization from 2014 to 2019, where associated costs net of rebates significantly increased to a disproportionately greater extent than the significant increase in utilization PUPM.

Health care utilization and costs associated with switching from DPP-4i to GLP-1RA or SGLT2i: an observational cohort study.

BACKGROUND: Because of improved clinical outcomes, recent American Diabetes Association guidelines recommend the use of newer antidiabetic agents-glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i)-by those with cardiovascular disease. It is unclear, however, how switching to these newer agents affects health care utilization and costs. OBJECTIVE: To compare health care utilization and costs between users of dipeptidyl peptidase-4 inhibitors (DPP-4i) who switch to GLP-1RA or SGLT2i and nonswitchers. METHODS: We used claims data from a large pharmacy benefit manager. Patients included were commercially insured adults with type 2 diabetes and a prescription claim for DPP-4i in 2016 or 2017. Using propensity score methods, we matched patients who switched to SGLT2i or GLP-1RA with those who remained on DPP-4i. Among matched samples, we conducted multivariable negative binomial regression to examine differences in the incidence of inpatient and emergency room (ER) visits and generalized linear regression to examine differences in health care costs. RESULTS: Among 47,953 patients who used DPP-4i in 2016 and 2017, 507 switched to SGLT2i and 808 switched to GLP-1RA. Propensity score matching of 1:6 resulted in 3,042 nonswitchers/507 switchers for the SGLT2i cohort and 4,848 nonswitchers/808 switchers for the GLP-1RA cohort. Switchers to SGLT2i experienced a 39% reduction (incidence rate ratio [IRR] = 0.61, 95% CI = 0.38-0.96), and GLP-1RA switchers experienced a 29% reduction (IRR = 0.71, 95% CI = 0.52-0.97) in inpatient hospitalizations. ER visit rates did not differ significantly between switchers and nonswitchers. Switchers to SGLT2i did not have statistically significant differences in medical or pharmacy costs compared with DPP-4i users, while switchers to GLP-1RA had significantly higher total pharmacy costs (adjusted difference of $2,453.10, 95% CI = $1,837.20-$3,069.00). CONCLUSIONS: Switching from DPP-4i to GLP-1RA or SGLT2i was associated with fewer hospitalizations; however, higher pharmacy costs may outweigh savings from reduced hospitalizations, especially for GLP-1RAs. As newer diabetes guidelines steer specific populations to these drug classes, it is important to optimize drug pricing to realize their true value. DISCLOSURES: No outside funding supported this study. Neilson, Good, Swart, and Huang are employees of UPMC Center for Value-Based Pharmacy Initiatives and High-Value Care. Parekh reports employment at UPMC until July 2019. Munshi and Henderson are employed by Express Scripts. Newman has no disclosures to report.

Efficacy and safety of tolperisone versus baclofen among Chinese patients with spasticity associated with spinal cord injury: a non-randomized retrospective study

There are many medications available to treat spasticity, but the tolerability of medications is the main issue for choosing the best treatment. The objectives of this study were to compare the efficacy and adverse effects of tolperisone compared to baclofen among patients with spasticity associated with spinal cord injury. Patients received baclofen plus physical therapy (BAF+PT, n=135) or tolperisone plus physical therapy (TOL+PT, n=116), or physical therapy alone (PT, n=180). The modified Ashworth scale score, the modified Medical Research Council score, the Barthel Index score, and the Disability Assessment scale score were improved (P<0.05 for all) in all the patients at the end of 6 weeks compared to before interventions. After 6 weeks, the overall coefficient of efficacy of the intervention(s) in the BAF+PT, TOL+PT, and PT groups were 1.15, 0.45, and 0.05, respectively. The patients of the BAF+PT group reported asthenia, drowsiness, and sleepiness and those of the TOL+PT group reported dyspepsia and epigastric pain as adverse effects. When comparing drug interventions to physical therapy alone, both baclofen plus physical therapy and tolperisone plus physical therapy played a significant role in the improvement of daily activities of patients. Nonetheless, baclofen plus physical therapy was tentatively effective. Tolperisone plus physical therapy was slightly effective. In addition, baclofen caused adverse effects related to the sedative manifestation (Level of Evidence: III; Technical Efficacy Stage: 4).

Early Use of Antibiotics Is Associated with a Lower Incidence of Necrotizing Enterocolitis in Preterm, Very Low Birth Weight Infants: The NEOMUNE-NeoNutriNet Cohort Study.

OBJECTIVE: To determine whether commencement of antibiotics within 3 postnatal days in preterm, very low birth weight (VLBW; ≤1500 g) infants is associated with the development of necrotizing enterocolitis (NEC). STUDY DESIGN: Preplanned statistical analyses were done to study the association between early antibiotic treatment and later NEC development, using the NEOMUNE-NeoNutriNet cohort of VLBW infants from 13 neonatal intensive care units (NICUs) in 5 continents (n = 2831). NEC incidence was compared between infants who received early antibiotics and those who did not, with statistical adjustments for NICU, gestational age, birth weight, sex, delivery mode, antenatal steroid use, Apgar score, and type and initiation of enteral nutrition. RESULTS: The incidence of NEC was 9.0% in the group of infants who did not receive early antibiotics (n = 269), compared with 3.9% in those who did receive early antibiotics (n = 2562). The incidence remained lower in the early antibiotic group after stepwise statistical adjustments for NICU (OR, 0.57; 95% CI, 0.35-0.94, P < .05) and other potential confounders (OR, 0.25; 95% CI, 0.12-0.47; P < .0001). CONCLUSIONS: In this large international cohort of preterm VLBW infants, a small proportion of infants did not receive antibiotics just after birth, and these infants had a higher incidence of NEC. It is important to better understand the role of such variables as time, type, and duration of antibiotic treatment on NEC incidence, immune development, gut colonization, and antibiotic resistance in the NICU.

Selenium protects against LPS-induced MC3T3-E1 cells apoptosis through modulation of microRNA-155 and PI3K/Akt signaling pathways.

Bone infection or osteomyelitis is usually a complication of inflammation-related traumatic bone injury. Selenium has been shown to have potential cytoprotective effects and the ability to reduce oxidative stress and apoptotic events in osteomyelitis, but the exact mechanism remains unclear. Here, we used LPS-induced apoptotic MC3T3-E1 cells and aimed to confirm selenium's protective effect on cell apoptosis as well as to investigate the underlying mechanisms of this role. Our investigation confirmed selenium-mediated inhibition of LPS-induced cell apoptosis and ROS accumulation in MC3T3-E1 cells. Upon selenium treatment, the bcl-2 levels were upregulated, while the levels of Bax and cyto-C were down-regulated. Furthermore, these effects were accompanied by the suppression of miR-155 and the phosphorylation of protein kinase B (Akt). A more in-depth study demonstrated that LY294002 (a specific inhibitor of PI3K), abolished the selenium-mediated cytoprotective effect of MC3T3-E1 cells against LPS-induced injury and down-regulation of miR-155. In general, these results demonstrated that selenium exerts a cytoprotective effect by attenuating cell apoptosis and oxidative damage via a PI3K/Akt/miR-155-dependent mechanism.

Evaluation of the sealing ability of different root canal sealers: a combined SEM and micro-CT study.

OBJECTIVE: The purpose of this study was to analyze the ability of multiple compounds to seal the dental tubules using scanning electron microscopy (SEM) and micro-computed tomogra-phy (micro-CT). MATERIAL AND METHODS: Twenty-four single-root human mandibular premolars were selected and instrumented with nickel-titanium rotary file and the final file size was #40/06. They were then randomly allocated into 2 groups, and all samples were filled with single cone gutta-percha (#40/06) and one of the tested sealers (AH Plus and EndoSequence BC sealers). All specimens were scanned using micro-CT and then three from each group were randomly selected for SEM analysis. RESULTS: According to SEM, both root canal sealers showed sufficient adaptation to dentin along the whole length of the root canal, though the coronal sections presented superior sealing than the apical sections. Micro porosity analyses revealed that the volume of closed pores and the surface of closed pores had the largest values in the coronal sections, followed by the middle and the apical sections for both sealants (p<0.05). However, no significant difference was observed for those two parameters between AH Plus and EndoSequence BC sealers in any of the three sections (p>0.05), whereas they were larger in the apical section when the AH Plus sealer was used. CONCLUSIONS: By using the single cone technique, neither EndoSequence or AH Plus pro-vides a porosity-free root canal filling. The EndoSequence BC sealer may have similar sealing abilities regarding the whole root canal as the AH Plus sealer. A better sealing effect could be obtained in the coronal and middle sections of a root canal than the apical part by using the tested sealers.

Evaluation of the sealing ability of different root canal sealers: a combined SEM and micro-CT study

Abstract Objective: The purpose of this study was to analyze the ability of multiple compounds to seal the dental tubules using scanning electron microscopy (SEM) and micro-computed tomogra-phy (micro-CT). Material and Methods: Twenty-four single-root human mandibular premolars were selected and instrumented with nickel-titanium rotary file and the final file size was #40/06. They were then randomly allocated into 2 groups, and all samples were filled with single cone gutta-percha (#40/06) and one of the tested sealers (AH Plus and EndoSequence BC sealers). All specimens were scanned using micro-CT and then three from each group were randomly selected for SEM analysis. Results: According to SEM, both root canal sealers showed sufficient adaptation to dentin along the whole length of the root canal, though the coronal sections presented superior sealing than the apical sections. Micro porosity analyses revealed that the volume of closed pores and the surface of closed pores had the largest values in the coronal sections, followed by the middle and the apical sections for both sealants (p<0.05). However, no significant difference was observed for those two parameters between AH Plus and EndoSequence BC sealers in any of the three sections (p>0.05), whereas they were larger in the apical section when the AH Plus sealer was used. Conclusions: By using the single cone technique, neither EndoSequence or AH Plus pro-vides a porosity-free root canal filling. The EndoSequence BC sealer may have similar sealing abilities regarding the whole root canal as the AH Plus sealer. A better sealing effect could be obtained in the coronal and middle sections of a root canal than the apical part by using the tested sealers.