The Impact of an Antimicrobial Stewardship Program on Days of Therapy in the Pediatric Center: An Interrupted Time-Series Analysis of a 19-Year Study.

BACKGROUND: We aimed to analyze the effects of an antimicrobial stewardship program (ASP) on the proportion of antimicrobial-resistant pathogens in bacteremia, antimicrobial use, and mortality in pediatric patients. METHODS: A retrospective single-center study was performed on pediatric inpatients under 19 years old who received systemic antimicrobial treatment from 2001 to 2019. A pediatric infectious disease attending physician started ASP in January 2008. The study period was divided into the pre-intervention (2001-2008) and the post-intervention (2009-2019) periods. The amount of antimicrobial use was defined as days of therapy per 1,000 patient-days, and the differences were compared using delta slope (= changes in slopes) between the two study periods by an interrupted time-series analysis. The proportion of resistant pathogens and the 30-day overall mortality rate were analyzed by the χ². RESULTS: The proportion of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae bacteremia increased from 17% (39 of 235) in the pre-intervention period to 35% (189 of 533) in the post-intervention period (P < 0.001). The total amount of antimicrobial use significantly decreased after the introduction of ASP (delta slope value = -16.5; 95% confidence interval [CI], -30.6 to -2.3; P = 0.049). The 30-day overall mortality rate in patients with bacteremia did not increase, being 10% (55 of 564) in the pre-intervention and 10% (94 of 941) in the post-intervention period (P = 0.881). CONCLUSION: The introduction of ASP for pediatric patients reduced the delta slope of the total antimicrobial use without increasing the mortality rate despite an increased incidence of ESBL-producing gram-negative bacteremia.

Neuronal ablation of GHSR mitigates diet-induced depression and memory impairment via AMPK-autophagy signaling-mediated inflammation.

Obesity is associated with chronic inflammation in the central nervous system (CNS), and neuroinflammation has been shown to have detrimental effects on mood and cognition. The growth hormone secretagogue receptor (GHSR), the biologically relevant receptor of the orexigenic hormone ghrelin, is primarily expressed in the brain. Our previous study showed that neuronal GHSR deletion prevents high-fat diet-induced obesity (DIO). Here, we investigated the effect of neuronal GHSR deletion on emotional and cognitive functions in DIO. The neuron-specific GHSR-deficient mice exhibited reduced depression and improved spatial memory compared to littermate controls under DIO. We further examined the cortex and hippocampus, the major regions regulating cognitive and emotional behaviors, and found that the neuronal deletion of GHSR reduced DIO-induced neuroinflammation by suppressing proinflammatory chemokines/cytokines and decreasing microglial activation. Furthermore, our data showed that neuronal GHSR deletion suppresses neuroinflammation by downregulating AMPK-autophagy signaling in neurons. In conclusion, our data reveal that neuronal GHSR inhibition protects against DIO-induced depressive-like behavior and spatial cognitive dysfunction, at least in part, through AMPK-autophagy signaling-mediated neuroinflammation.

Plasma-Activated Media Produced by a Microwave-Excited Atmospheric Pressure Plasma Jet Is Effective against Cisplatin-Resistant Human Bladder Cancer Cells In Vitro.

Media exposed to atmospheric pressure plasma (APP) produce reactive oxygen and nitrogen species (RONS), with hydrogen peroxide (H2O2), nitrite (NO2-), and nitrate (NO3-) being among the most detected species due to their relatively long lifetime. In this study, a standardized microwave-excited (ME) APP jet (APPJ) source was employed to produce gaseous RONS to treat liquid samples. The source was a commercially available plasma jet, which generated argon plasma utilizing a coaxial transmission line resonator at the operating frequency of 2.45 GHz. An ultraviolet-visible spectrophotometer was used to measure the concentrations of H2O2 and NO3- in plasma-activated media (PAM). Three different types of media (deionized water, Hank's balanced salt solution, and cell culture solution Dulbecco's modified eagles medium [DMEM]) were utilized as liquid samples. Among these media, the plasma-treated DMEM was observed to have the highest levels of H2O2 and NO3-. Subsequently, the feasibility of using argon ME-APPJ-activated DMEM (PAM) as an adjuvant to enhance the therapeutic effects of cisplatin on human bladder cancer cells (T-24) was investigated. Various cancer cell lines, including T-24 cells, treated with PAM were observed in vitro for changes in cell viability using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. A viability reduction was detected in the various cancer cells after incubation in PAM. Furthermore, the study's results revealed that PAM was effective against cisplatin-resistant T-24 cells in vitro. In addition, a possible connection between HER expression and cell viability was sketched.

Brain region dependent molecular signatures and myelin repair following chronic demyelination.

Multiple sclerosis (MS) is the most prevalent demyelinating disease of the central nervous system, characterized by myelin destruction, axonal degeneration, and progressive loss of neurological functions. Remyelination is considered an axonal protection strategy and may enable functional recovery, but the mechanisms of myelin repair, especially after chronic demyelination, remain poorly understood. Here, we used the cuprizone demyelination mouse model to investigate spatiotemporal characteristics of acute and chronic de- and remyelination and motor functional recovery following chronic demyelination. Extensive remyelination occurred after both the acute and chronic insults, but with less robust glial responses and slower myelin recovery in the chronic phase. Axonal damage was found at the ultrastructural level in the chronically demyelinated corpus callosum and in remyelinated axons in the somatosensory cortex. Unexpectedly, we observed the development of functional motor deficits after chronic remyelination. RNA sequencing of isolated brain regions revealed significantly altered transcripts across the corpus callosum, cortex and hippocampus. Pathway analysis identified selective upregulation of extracellular matrix/collagen pathways and synaptic signaling in the chronically de/remyelinating white matter. Our study demonstrates regional differences of intrinsic reparative mechanisms after a chronic demyelinating insult and suggests a potential link between long-term motor function alterations and continued axonal damage during chronic remyelination. Moreover, the transcriptome dataset of three brain regions and over an extended de/remyelination period provides a valuable platform for a better understanding of the mechanisms of myelin repair as well as the identification of potential targets for effective remyelination and neuroprotection for progressive MS.

Differential Sensitivity of Melanoma Cells and Their Non-Cancerous Counterpart to Cold Atmospheric Plasma-Induced Reactive Oxygen and Nitrogen Species.

Despite continuous progress in therapy, melanoma is one of the most aggressive and malignant human tumors, often relapsing and metastasizing to almost all organs. Cold atmospheric plasma (CAP) is a novel anticancer tool that utilizes abundant reactive oxygen and nitrogen species (RONS) being deposited on the target cells and tissues. CAP-induced differential effects between non-cancerous and cancer cells were comparatively examined. Melanoma and non-cancerous skin fibroblast cells (counterparts; both cell types were isolated from the same patient) were used for plasma-cell interactions. The production of intracellular RONS, such as nitric oxide (NO), hydroxyl radical (•OH), and hydrogen peroxide (H2O2), increased remarkably only in melanoma cancer cells. It was observed that cancer cells morphed from spread to round cell shapes after plasma exposure, suggesting that they were more affected than non-cancerous cells in the same plasma condition. Immediately after both cell types were treated with plasma, there were no differences in the amount of extracellular H2O2 production, while Hanks' balanced salt solution-containing cancer cells had lower concentrations of H2O2 than that of non-cancerous cells at 1 h after treatment. The melanoma cells seemed to respond to CAP treatment with a greater rise in RONS and a higher consumption rate of H2O2 than homologous non-cancerous cells. These results suggest that differential sensitivities of non-cancerous skin and melanoma cells to CAP-induced RONS can enable the applicability of CAP in anticancer therapy.

Linking Public Health and Public Safety Data on Co-occurring Disorders Among Adults in Hawaii's Criminal Justice System.

To better understand the behavioral health treatment needs of adults involved in the criminal justice system and to improve the continuum of services provided to this vulnerable population, Hawaii initiated a data linkage project that connects substance use and mental health data from the state Department of Public Safety with behavioral health treatment data from the state Department of Health for the State of Hawaii. Specifically, this linkage project begins to examine behavioral health treatment levels recommended by the criminal justice system and Hawaii State Hospital inpatient psychiatric admissions. We provide a preliminary summary on individuals who were both involved in the criminal justice system and received court-ordered inpatient psychiatric treatment and outline data governance procedures, future directions, and practice recommendations.

Myeloid caspase-8 restricts RIPK3-dependent proinflammatory IL-1ß production and CD4 T cell activation in autoimmune demyelination.

Caspase-8 functions at the crossroad of programmed cell death and inflammation. Here, using genetic approaches and the experimental autoimmune encephalomyelitis model of inflammatory demyelination, we identified a negative regulatory pathway for caspase-8 in infiltrated macrophages whereby it functions to restrain interleukin (IL)-1ß-driven autoimmune inflammation. Caspase-8 is partially activated in macrophages/microglia in active lesions of multiple sclerosis. Selective ablation of Casp8 in myeloid cells, but not microglia, exacerbated autoimmune demyelination. Heightened IL-1ß production by caspase-8-deficient macrophages underlies exacerbated activation of encephalitogenic T cells and production of GM-CSF and interferon-γ. Mechanistically, IL-1ß overproduction by primed caspase-8-deficient macrophages was mediated by RIPK1/RIPK3 through the engagement of NLRP3 inflammasome and was independent of cell death. When instructed by autoreactive CD4 T cells in the presence of antigen, caspase-8-deficient macrophages, but not their wild-type counterparts, released significant amount of IL-1ß that in turn acted through IL-1R to amplify T cell activation. Moreover, the worsened experimental autoimmune encephalomyelitis progression in myeloid Casp8 mutant mice was completely reversed when Ripk3 was simultaneously deleted. Together, these data reveal a functional link between T cell-driven autoimmunity and inflammatory IL-1ß that is negatively regulated by caspase-8, and suggest that dysregulation of the pathway may contribute to inflammatory autoimmune diseases, such as multiple sclerosis.

Effects of exposure to ambient air pollution on pulmonary function impairment in Korea: the 2007-2017 Korea National Health and Nutritional Examination Survey.

OBJECTIVES: This study aimed to investigate the association between pulmonary function and air pollution using 2007-2017 data from the Korea National Health and Nutrition Examination Survey, a nationwide cross-sectional representative survey. METHODS: A total of 27,378 participants that had sampling weights from a complex sample survey were included in this study. Using the data for forced expiratory volume in 1 second and forced vital capacity, the participants with pulmonary function impairment were classified according to the criteria of restrictive lung disease and chronic obstructive pulmonary disease (COPD). Exposure to ambient air pollution was estimated using the Community Multiscale Air Quality model. Multivariate linear and logistic regression analyses with complex samples were used to determine the associations between pulmonary function and air pollution after adjusting for covariates. RESULTS: In total, 13.2% of the participants aged >40 years had COPD, and 10.7% were classified as being in the restrictive lung disease group. According to the multivariate logistic regression model, the odds ratios for the fourth quartiles of particulate matter less than 10 µm in diameter (PM10), particulate matter less than 2.5 µm in diameter (PM2.5) and carbon monoxide (CO) with a 2-year lag period were 1.203 (95% confidence interval [CI], 1.036 to 1.396), 1.283 (95% CI, 1.101 to1.495), and 1.292 (95% CI, 1.110 to 1.504), respectively, using the restrictive lung disease group as an event after adjusting for covariates in the complex sample. CONCLUSIONS: Long-term exposure to PM10, PM2.5, and CO was significantly associated with pulmonary function, especially restrictive lung disease.

STAT3 signaling in myeloid cells promotes pathogenic myelin-specific T cell differentiation and autoimmune demyelination.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system. Dysregulation of STAT3, a transcription factor pivotal to various cellular processes including Th17 cell differentiation, has been implicated in MS. Here, we report that STAT3 is activated in infiltrating monocytic cells near active MS lesions and that activation of STAT3 in myeloid cells is essential for leukocyte infiltration, neuroinflammation, and demyelination in experimental autoimmune encephalomyelitis (EAE). Genetic disruption of Stat3 in peripheral myeloid lineage cells abrogated EAE, which was associated with decreased antigen-specific T helper cell responses. Myeloid cells from immunized Stat3 mutant mice exhibited impaired antigen-presenting functions and were ineffective in driving encephalitogenic T cell differentiation. Single-cell transcriptome analyses of myeloid lineage cells from preclinical wild-type and mutant mice revealed that loss of myeloid STAT3 signaling disrupted antigen-dependent cross-activation of myeloid cells and T helper cells. This study identifies a previously unrecognized requisite for myeloid cell STAT3 in the activation of myelin-reactive T cells and suggests myeloid STAT3 as a potential therapeutic target for autoimmune demyelinating disease.

Comparing Birth Outcomes in Hawai'i between US- and Foreign-Born Women.

The objective of this study is to examine the relationship between maternal nativity status and preterm birth (PTB) or low birth weight (LBW) for Hawai'i resident mothers, to compare these relationships across different maternal race/ethnicity groups, and to identify other potential risk and protective factors related to PTB and LBW. Using the 2004 Natality Birth Data from the National Vital Statistic System of the National Center for Health Statistics, crude and adjusted odds ratios were calculated using logistic regression to determine maternal racial/ethnic-specific nativity effects on PTB and LBW. Other Asian or Pacific Islander foreign-born mothers had higher unadjusted rates of PTB, and Samoan foreign-born mothers had lower rates of LBW after adjusting for the socio-demographic covariates compared to their native-born counterparts. Given the limitation of this study particularly relating to data quality, further research is needed to identify socio-contextual factors that are involved in the relationship between nativity status and PTB/LBW.

Severe hematuria in a hematopoietic cell transplant recipient caused by Ureaplasma urealyticum not by BK virus or adenovirus infection.

A 17-year-old male with acute lymphoblastic leukemia developed severe hematuria and scrotal swelling after haploidentical hematopoietic cell transplantation (HCT). Urine culture was negative. BK virus and adenovirus were negative. However, Ureaplasma urealyticum was detected. He showed dramatic improvement after doxycycline treatment. This is the first report in the literature of hemorrhagic cystitis caused by U. urealyticum in a HCT recipient. In HCT recipients with hemorrhagic cystitis, U. urealyticum should be considered as a potential cause.

A Three-Dimensional Arrayed Microfluidic Blood-Brain Barrier Model With Integrated Electrical Sensor Array.

OBJECTIVE: The blood-brain barrier (BBB) poses a unique challenge to the development of therapeutics against neurological disorders due to its impermeabi-lity to most of the chemical compounds. Most in vitro BBB models have limitations in mimicking in vivo conditions and functions. Here, we show a co-culture microfluidic BBB-on-a-chip that provides interactions between neurovascular endothelial cells and neuronal cells across a porous polycarbonate membrane, which better mimics the in vivo conditions, as well as allows in vivo level shear stress to be applied. METHODS: A 4 × 4 intersecting microchannel array forms 16 BBB sites on a chip, with a multielectrode array integrated to measure the transendothelial electrical resistance (TEER) from all 16 different sites, which allows label-free real-time analysis of the barrier function. Primary mouse endothelial cells and primary astrocytes were co-cultured in the chip while applying in vivo level shear stress. The chip allows the barrier function to be analyzed through TEER measurement, dextran permeability, as well as immunostaining. RESULTS: Co-culture between astrocytes and endothelial cells, as well as in vivo level shear stress applied, led to the formation of tighter junctions and significantly lower barrier permeability. Moreover, drug testing with histamine showed increased permeability when using only endothelial cells compared to almost no change when using co-culture. CONCLUSION: Results show that the developed BBB chip more closely mimics the in vivo BBB environment. SIGNIFICANCE: The developed multisite BBB chip is expected to be used for screening drug by more accurately predicting their permeability through BBB as well as their toxicity.

Functional antagonism of sphingosine-1-phosphate receptor 1 prevents cuprizone-induced demyelination.

Recent evidence suggests that the oral drug Fingolimod (FTY720) for relapsing-remitting multiple sclerosis (MS) may act directly on the central nervous system (CNS) and modulate disease pathogenesis and progression in experimental models of MS. However, the specific subtype of sphingosine-1-phosphate (S1P) receptors that mediates the effect of FTY720 on the CNS cells has not been fully elucidated. Here, we report that S1P receptor 1 (S1PR1) is elevated in reactive astrocytes in an autoimmunity independent mouse model of MS and that selective S1PR1 modulation is sufficient to ameliorate the loss of oligodendrocytes and demyelination. The non-selective S1PR modulator, FTY720, or a short-lived S1PR1-specific modulator, CYM5442, was administered daily to mice while on cuprizone diet. Both FTY720- and CYM5422-treated mice displayed a significant reduction in oligodendrocyte apoptosis and astrocyte and microglial activation in comparison to vehicle-treated groups, which was associated with decreased production of proinflammatory mediators and down-regulation of astrocytic S1PR1 protein. Interestingly, S1PR1 modulation during the early phase of cuprizone intoxication was required to suppress oligodendrocyte death and consequent demyelination as drug treatment from 10 days after the initiation of cuprizone feeding was no longer effective. CYM5442 treatment during the brief cuprizone exposure significantly prevented Il-1ß, Il-6, Cxcl10, and Cxcl3 induction, resulting in suppression of subsequent reactive gliosis and demyelination. Our study identifies functional antagonism of S1PR1 as a major mechanism for the protective effect of FTY720 in the cuprizone model and suggests pathogenic contributions of astrocyte S1PR1 signaling in primary demyelination and its potential as a therapeutic target for CNS inflammation.

Aligning Funding and Need for Family Planning: A Diagnostic Methodology.

With limited international resources for family planning, donors must decide how to allocate their funds to different countries. How can a donor for family planning decide whether countries are adequately prioritized for funding? This article proposes an ordinal ranking framework to identify under-prioritized countries by rank-ordering countries by their need for family planning and separately rank-ordering them by their development assistance for family planning. Countries for which the rank of the need for family planning is lower than the rank of its funding are deemed under-prioritized. We implement this diagnostic methodology to identify under-prioritized countries that have a higher need but lower development assistance for family planning. This approach indicates whether a country is receiving less compared to other countries with similar levels of need.

Activation of oligodendroglial Stat3 is required for efficient remyelination.

Multiple sclerosis is the most prevalent demyelinating disease of the central nervous system (CNS) and is histologically characterized by perivascular demyelination as well as neurodegeneration. While the degree of axonal damage is correlated with clinical disability, it is believed that remyelination can protect axons from degeneration and slow disease progression. Therefore, understanding the intricacies associated with myelination and remyelination may lead to therapeutics that can enhance the remyelination process and slow axon degeneration and loss of function. Ciliary neurotrophic factor (CNTF) family cytokines such as leukemia inhibitory factor (LIF) and interleukin 11 (IL-11) are known to promote oligodendrocyte maturation and remyelination in experimental models of demyelination. Because CNTF family member binding to the gp130 receptor results in activation of the JAK2/Stat3 pathway we investigated the necessity of oligodendroglial Stat3 in transducing the signal required for myelination and remyelination. We found that Stat3 activation in the CNS coincides with myelination during development. Stimulation of oligodendrocyte precursor cells (OPCs) with CNTF or LIF promoted OPC survival and final differentiation, which was completely abolished by pharmacologic blockade of Stat3 activation with JAK2 inhibitor. Similarly, genetic ablation of Stat3 in oligodendrocyte lineage cells prevented CNTF-induced OPC differentiation in culture. In vivo, while oligodendroglial Stat3 signaling appears to be dispensable for developmental CNS myelination, it is required for oligodendrocyte regeneration and efficient remyelination after toxin-induced focal demyelination in the adult brain. Our data suggest a critical function for oligodendroglial Stat3 signaling in myelin repair.

Epidemiology of scrub typhus and the eschars patterns in South Korea from 2008 to 2012.

In South Korea, scrub typhus is the most common acute febrile illness in autumn. We analyzed scrub typhus cases reported from 2008 to 2012 to describe the epidemiology of scrub typhus as well as eschar patterns. A total of 30,478 cases were reported from 2008 to 2012; the incidence rates were higher in the southern and western regions of South Korea. The common clinical symptoms of confirmed scrub typhus cases from 2010 to 2012 were fever/chills (95.2%), eschars (78.9%), and myalgia (61.7%). The primary sites of eschars were the lower extremities (19.0%), abdomen/waist (13.4%), and axilla (11.5%) in men and the shoulder/frontal chest (15.1%), lower extremities (14.5%), and abdomen/waist (13.6%) in women. Regardless of gender, eschars tended to be more on the lower extremities among the leisure activities group. Among the occupational farm work group, who usually lived in rural areas, eschars appeared most frequently on the abdomen/waist in men and on the shoulder/frontal chest in women. Eschar patterns were influenced by gender and activities. These results could facilitate the prevention of scrub typhus and clarify the current status of scrub typhus in South Korea.

Axon length quantification microfluidic culture platform for growth and regeneration study.

To fully understand how external biomolecular environment influences axon growth, a method that can easily quantify the extent of axon growth as well as locally control their biomolecular environment is critically needed. Here, we describe a microfluidic culture platform capable of isolating CNS axons from neuronal somata for localized biomolecular manipulation as well as providing linearly guided axon growths for simple and easy quantification of the axon growth length. The axon isolation and guidance capability combined with the multi-compartment configuration make this platform ideal for investigating and screening drugs or other molecular factors that promote axon growth as well as regeneration.

Direct visualization of membrane architecture of myelinating cells in transgenic mice expressing membrane-anchored EGFP.

Myelinogenesis is a complex process that involves substantial and dynamic changes in plasma membrane architecture and myelin interaction with axons. Highly ramified processes of oligodendrocytes in the central nervous system (CNS) make axonal contact and then extrapolate to wrap around axons and form multilayer compact myelin sheathes. Currently, the mechanisms governing myelin sheath assembly and axon selection by myelinating cells are not fully understood. Here, we generated a transgenic mouse line expressing the membrane-anchored green fluorescent protein (mEGFP) in myelinating cells, which allow live imaging of details of myelinogenesis and cellular behaviors in the nervous systems. mEGFP expression is driven by the promoter of 2'-3'-cyclic nucleotide 3'-phosphodiesterase (CNP) that is expressed in the myelinating cell lineage. Robust mEGFP signals appear in the membrane processes of oligodendrocytes in the CNS and Schwann cells in the peripheral nervous system (PNS), wherein mEGFP expression defines the inner layers of myelin sheaths and Schmidt-Lanterman incisures in adult sciatic nerves. In addition, mEGFP expression can be used to track the extent of remyelination after demyelinating injury in a toxin-induced demyelination animal model. Taken together, the membrane-anchored mEGFP expression in the new transgenic line would facilitate direct visualization of dynamic myelin membrane formation and assembly during development and process remodeling during remyelination after various demyelinating injuries.