Effects of implementation of an online comprehensive antimicrobial-stewardship program in ICUs: A longitudinal study

AbstractBackground/purposeThe long-term effects of antimicrobial-stewardship programs in the intensive care units (ICUs) have not been adequately examined. We evaluated the impact of an online comprehensive antimicrobial stewardship program (OCASP) on the outcomes of patients in 200-bed medical/surgical ICUs over the course of 11 years.MethodsWe analyzed the records of adult patients admitted to ICUs during the 5 years before (n = 27,499) and the 6 years after (n = 33,834) implementation of an OCASP. Antimicrobial consumption, expenditures, duration of treatment, incidence of healthcare-associated infections (HAIs), prevalence of HAIs caused by antimicrobial-resistant strains, and crude or sepsis-related mortality of patients were analyzed. Segmented regression analyses of interrupted time series were used to assess the significance of changes in antimicrobial use.ResultsCompared to the patients in the pre-OCASP period, the patients in the post-OCASP period were older, had greater disease severity, longer ICU stays, and were more likely to receive antimicrobials, but had lower antimicrobial expenditures and crude and sepsis-related mortality. The trend of overall antimicrobial use [slope of defined daily dose/1000 patient-days vs. time) increased significantly before OCASP implementation (p < 0.001), but decreased significantly after implementation (p < 0.01). The administration duration of all classes of antibiotics were significantly shorter (p < 0.001) and the incidences of HAIs were significantly lower (p < 0.001) after implementation. However, there was an increase in the proportion of HAIs caused by carbapenem-resistant Acinetobacter baumannii relative to all A. baumannii infections.ConclusionImplementation of an OCASP in the ICUs reduced antimicrobial consumption and expenditures, but did not compromise healthcare quality

Microfluidic Perfusion for Regulating Diffusible Signaling in Stem Cells

Background Autocrine & paracrine signaling are widespread both in vivo and in vitro, and are particularly important in embryonic stem cell (ESC) pluripotency and lineage commitment. Although autocrine signaling via fibroblast growth factor-4 (FGF4) is known to be required in mouse ESC (mESC) neuroectodermal specification, the question of whether FGF4 autocrine signaling is sufficient, or whether other soluble ligands are also involved in fate specification, is unknown. The spatially confined and closed-loop nature of diffusible signaling makes its experimental control challenging; current experimental approaches typically require prior knowledge of the factor/receptor in order to modulate the loop. A new approach explored in this work is to leverage transport phenomena at cellular resolution to downregulate overall diffusible signaling through the physical removal of cell-secreted ligands. Methodology/Principal Findings We develop a multiplex microfluidic platform to continuously remove cell-secreted (autocrine\paracrine) factors to downregulate diffusible signaling. By comparing cell growth and differentiation in side-by-side chambers with or without added cell-secreted factors, we isolate the effects of diffusible signaling from artifacts such as shear, nutrient depletion, and microsystem effects, and find that cell-secreted growth factor(s) are required during neuroectodermal specification. Then we induce FGF4 signaling in minimal chemically defined medium (N2B27) and inhibit FGF signaling in fully supplemented differentiation medium with cell-secreted factors to determine that the non-FGF cell-secreted factors are required to promote growth of differentiating mESCs. Conclusions/Significance Our results demonstrate for the first time that flow can downregulate autocrine\paracrine signaling and examine sufficiency of extracellular factors. We show that autocrine\paracrine signaling drives neuroectodermal commitment of mESCs through both FGF4-dependent and -independent pathways. Overall, by uncovering autocrine\paracrine processes previously hidden in conventional culture systems, our results establish microfluidic perfusion as a technique to study and manipulate diffusible signaling in cell systems.National Institutes of Health (U.S.) (NIH grant No. EB007278)Swiss National Science FoundationSwiss National Science Foundatio

Postmarketing surveillance of sumatriptan : patient population, efficacy, and adverse effects

A postmarketing surveillance survey of sumatriptan use comprised 32 questions including patient demographics, headache history, and sumatriptan experience. One hundred and forty-one questionnaires were sent out, and 109 patients responded; a total of 108 patients were included in the data analysis. When compared with the national migraine population, on a percentage basis, significantly more African-Americans, females, young patients (less 45 years of age), and patients with higher mean incomes (\u3e$45,000) were found in the present study of those taking sumatriptan (p Males (N=8) and females (N=55) had a significantly different percentage of relief from the second dose of 94.7%±7.1 and 83.5%±24.4, respectively (p=0.01). An average percent of pain relief from the first dose in those weighing less or greater than 144 pounds was 76.5%±28.3 and 86.9%±16.4, respectively (p=0.023). The incidence of the adverse effects reported in this study was significantly greater than those reported in the literature (p\u3c0.005)

Postmarketing surveillance of sumatriptan : patient population, efficacy, and adverse effects

A postmarketing surveillance survey of sumatriptan use comprised 32 questions including patient demographics, headache history, and sumatriptan experience. One hundred and forty-one questionnaires were sent out, and 109 patients responded; a total of 108 patients were included in the data analysis. When compared with the national migraine population, on a percentage basis, significantly more African-Americans, females, young patients (less 45 years of age), and patients with higher mean incomes (\u3e$45,000) were found in the present study of those taking sumatriptan (p Males (N=8) and females (N=55) had a significantly different percentage of relief from the second dose of 94.7%±7.1 and 83.5%±24.4, respectively (p=0.01). An average percent of pain relief from the first dose in those weighing less or greater than 144 pounds was 76.5%±28.3 and 86.9%±16.4, respectively (p=0.023). The incidence of the adverse effects reported in this study was significantly greater than those reported in the literature (p\u3c0.005)

Effects of implementation of an online comprehensive antimicrobial-stewardship program in ICUs: A longitudinal study

Background/purpose: The long-term effects of antimicrobial-stewardship programs in the intensive care units (ICUs) have not been adequately examined. We evaluated the impact of an online comprehensive antimicrobial stewardship program (OCASP) on the outcomes of patients in 200-bed medical/surgical ICUs over the course of 11 years. Methods: We analyzed the records of adult patients admitted to ICUs during the 5 years before (n = 27,499) and the 6 years after (n = 33,834) implementation of an OCASP. Antimicrobial consumption, expenditures, duration of treatment, incidence of healthcare-associated infections (HAIs), prevalence of HAIs caused by antimicrobial-resistant strains, and crude or sepsis-related mortality of patients were analyzed. Segmented regression analyses of interrupted time series were used to assess the significance of changes in antimicrobial use. Results: Compared to the patients in the pre-OCASP period, the patients in the post-OCASP period were older, had greater disease severity, longer ICU stays, and were more likely to receive antimicrobials, but had lower antimicrobial expenditures and crude and sepsis-related mortality. The trend of overall antimicrobial use [slope of defined daily dose/1000 patient-days vs. time) increased significantly before OCASP implementation (p < 0.001), but decreased significantly after implementation (p < 0.01). The administration duration of all classes of antibiotics were significantly shorter (p < 0.001) and the incidences of HAIs were significantly lower (p < 0.001) after implementation. However, there was an increase in the proportion of HAIs caused by carbapenem-resistant Acinetobacter baumannii relative to all A. baumannii infections. Conclusion: Implementation of an OCASP in the ICUs reduced antimicrobial consumption and expenditures, but did not compromise healthcare quality

Predictors of Acute Kidney Disease Severity in Hospitalized Patients with Acute Kidney Injury

Acute kidney disease (AKD) forms part of the continuum of acute kidney injury (AKI) and worsens clinical outcomes. Currently, the predictors of AKD severity have yet to be established. We conducted a retrospective investigation involving 310 hospitalized patients with AKI and stratified them based on the AKD stages defined by the Acute Dialysis Quality Initiative criteria. Demographic, clinical, hematologic, and biochemical profiles, as well as 30-day outcomes, were compared between subgroups. In the analysis, the use of offending drugs (odds ratio, OR (95% confidence interval, CI), AKD stage 3 vs. non-AKD, 3.132 (1.304–7.526), p = 0.011, AKD stage 2 vs. non-AKD, 2.314 (1.049–5.107), p = 0.038), high AKI severity (OR (95% CI), AKD stage 3 vs. non-AKD, 6.214 (2.658–14.526), p p = 0.049) were identified as independent predictors of AKD severity. Moreover, a higher AKD severity was associated with higher 30-day mortality and lower dialysis-independent survival rates. In conclusion, our study demonstrated that offending drug use, AKI severity, and early dialysis requirement were independent predictors of AKD severity, and high AKD severity had negative impact on post-AKI outcomes

DataSheet_1_Outcomes of “sandwich” chemoradiotherapy compared with chemotherapy alone for the adjuvant treatment of FIGO stage III endometrial cancer.pdf

ObjectiveTo analyze and compare outcomes of adjuvant chemoradiotherapy in patients with International Federation of Gynecology and Obstetrics (FIGO) stage III endometrial cancer (EC) patients using the “Sandwich” sequence and chemotherapy (CT) alone.MethodsFrom, 2005 to, 2019, we retrospectively reviewed 80 patients with FIGO stage III EC who received treatment at our institute. We analyzed 66 patients who had undergone complete surgical staging followed by adjuvant treatment with sandwich chemoradiotherapy (39 patients) and CT alone (27 patients). The 5-year overall survival (OS), progression-free survival (PFS), and disease-specific survival (DSS) were calculated using the Kaplan–Meier method. Additional prognostic factors were analyzed using Cox proportional hazards regression.ResultsHerein, the analysis was conducted using 66 patients with a median follow-up period of 50 and 85 months in the sandwich and CT-alone arms. Comparing the sandwich sequence and CT-alone groups, the 5-year OS and PFS were 87% vs. 70% (p = 0.097) and 77% vs. 65% (p = 0.209), respectively. The sandwich therapy conferred an improved 5-year DSS (92% vs. 70%, p = 0.041) and a lower local recurrence rate (0% vs. 11%, p = 0.031). In multivariable analyses, grade 3 histology and deep myometrial invasion were independent risk factors for 5-year OS and DSS. The sandwich sequence was a positive predictor for 5-year DSS (hazard ratio [HR] = 0.23, p = 0.029). The sandwich arm demonstrated higher acute hematologic toxicity than the CT-alone arm. CT dose delay/reduction and treatment completion rates were similar in both groups.ConclusionFor patients with stage III EC, postoperative sandwich chemoradiotherapy appears to offer a superior 5-year DSS and local control with tolerable toxicity when compared with CT alone.</p

DataSheet_3_Methotrexate inhibition of SARS-CoV-2 entry, infection and inflammation revealed by bioinformatics approach and a hamster model.xlsx

BackgroundDrug repurposing is a fast and effective way to develop drugs for an emerging disease such as COVID-19. The main challenges of effective drug repurposing are the discoveries of the right therapeutic targets and the right drugs for combating the disease.MethodsHere, we present a systematic repurposing approach, combining Homopharma and hierarchal systems biology networks (HiSBiN), to predict 327 therapeutic targets and 21,233 drug-target interactions of 1,592 FDA drugs for COVID-19. Among these multi-target drugs, eight candidates (along with pimozide and valsartan) were tested and methotrexate was identified to affect 14 therapeutic targets suppressing SARS-CoV-2 entry, viral replication, and COVID-19 pathologies. Through the use of in vitro (EC50 = 0.4 μM) and in vivo models, we show that methotrexate is able to inhibit COVID-19 via multiple mechanisms.ResultsOur in vitro studies illustrate that methotrexate can suppress SARS-CoV-2 entry and replication by targeting furin and DHFR of the host, respectively. Additionally, methotrexate inhibits all four SARS-CoV-2 variants of concern. In a Syrian hamster model for COVID-19, methotrexate reduced virus replication, inflammation in the infected lungs. By analysis of transcriptomic analysis of collected samples from hamster lung, we uncovered that neutrophil infiltration and the pathways of innate immune response, adaptive immune response and thrombosis are modulated in the treated animals.ConclusionsWe demonstrate that this systematic repurposing approach is potentially useful to identify pharmaceutical targets, multi-target drugs and regulated pathways for a complex disease. Our findings indicate that methotrexate is established as a promising drug against SARS-CoV-2 variants and can be used to treat lung damage and inflammation in COVID-19, warranting future evaluation in clinical trials.</p

DataSheet_1_Methotrexate inhibition of SARS-CoV-2 entry, infection and inflammation revealed by bioinformatics approach and a hamster model.xlsx

BackgroundDrug repurposing is a fast and effective way to develop drugs for an emerging disease such as COVID-19. The main challenges of effective drug repurposing are the discoveries of the right therapeutic targets and the right drugs for combating the disease.MethodsHere, we present a systematic repurposing approach, combining Homopharma and hierarchal systems biology networks (HiSBiN), to predict 327 therapeutic targets and 21,233 drug-target interactions of 1,592 FDA drugs for COVID-19. Among these multi-target drugs, eight candidates (along with pimozide and valsartan) were tested and methotrexate was identified to affect 14 therapeutic targets suppressing SARS-CoV-2 entry, viral replication, and COVID-19 pathologies. Through the use of in vitro (EC50 = 0.4 μM) and in vivo models, we show that methotrexate is able to inhibit COVID-19 via multiple mechanisms.ResultsOur in vitro studies illustrate that methotrexate can suppress SARS-CoV-2 entry and replication by targeting furin and DHFR of the host, respectively. Additionally, methotrexate inhibits all four SARS-CoV-2 variants of concern. In a Syrian hamster model for COVID-19, methotrexate reduced virus replication, inflammation in the infected lungs. By analysis of transcriptomic analysis of collected samples from hamster lung, we uncovered that neutrophil infiltration and the pathways of innate immune response, adaptive immune response and thrombosis are modulated in the treated animals.ConclusionsWe demonstrate that this systematic repurposing approach is potentially useful to identify pharmaceutical targets, multi-target drugs and regulated pathways for a complex disease. Our findings indicate that methotrexate is established as a promising drug against SARS-CoV-2 variants and can be used to treat lung damage and inflammation in COVID-19, warranting future evaluation in clinical trials.</p