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Consensus guidelines for hospitalized, non-severe community-acquired pneumonia (CAP) recommend empiric macrolide + β-lactam or respiratory fluoroquinolone monotherapy in patients with no risk factors for resistant organisms. In patients with allergies or contraindications, doxycycline + β-lactam is a recommended alternative. The purpose of this study was to compare differences in outcomes among guideline-recommended regimens in this population. This retrospective, multicenter cohort study included patients ≥18 years of age with CAP who received respiratory fluoroquinolone monotherapy, empiric macrolide + β-lactam, or doxycycline + β-lactam. Major exclusion criteria included patients with immunocompromising conditions, requiring vasopressors or invasive mechanical ventilation within 48 hours of admission, and receiving less than 2 days of total antibiotic therapy. The primary outcome was in-hospital mortality. Secondary outcomes included clinical failure, 14- and 30-day hospital readmission, and hospital length of stay. Safety outcomes included incidence of new Clostridioides difficile infection and aortic aneurysm ruptures. Of 4685 included patients, 1722 patients received empiric respiratory fluoroquinolone monotherapy, 159 received empiric doxycycline + β-lactam, and 2804 received empiric macrolide + β-lactam. Incidence of in-hospital mortality was not observed to be significantly different among empiric regimens (doxycycline + β-lactam group: 1.9% vs macrolide + β-lactam: 1.9% vs respiratory fluoroquinolone monotherapy: 1.5%, P = 0.588). No secondary outcomes were observed to differ significantly among groups. We observed no differences in clinical or safety outcomes among three guideline-recommended empiric CAP regimens. Empiric doxycycline + β-lactam may be a safe empiric regimen for hospitalized CAP patients with non-severe CAP, although additional research is needed to corroborate these observations with larger samples.

The NCEP Climate Forecast System Reanalysis (CFSR) was completed for the 31-yr period from 1979 to 2009, in January 2010. The CFSR was designed and executed as a global, high-resolution coupled atmosphere–ocean–land surface–sea ice system to provide the best estimate of the state of these coupled domains over this period. The current CFSR will be extended as an operational, real-time product into the future. New features of the CFSR include 1) coupling of the atmosphere and ocean during the generation of the 6-h guess field, 2) an interactive sea ice model, and 3) assimilation of satellite radiances by the Gridpoint Statistical Interpolation (GSI) scheme over the entire period. The CFSR global atmosphere resolution is ~38 km (T382) with 64 levels extending from the surface to 0.26 hPa. The global ocean's latitudinal spacing is 0.25° at the equator, extending to a global 0.5° beyond the tropics, with 40 levels to a depth of 4737 m. The global land surface model has four soil levels and the global sea ice model has three layers. The CFSR atmospheric model has observed variations in carbon dioxide (CO₂) over the 1979–2009 period, together with changes in aerosols and other trace gases and solar variations. Most available in situ and satellite observations were included in the CFSR. Satellite observations were used in radiance form, rather than retrieved values, and were bias corrected with “spin up” runs at full resolution, taking into account variable CO₂ concentrations. This procedure enabled the smooth transitions of the climate record resulting from evolutionary changes in the satellite observing system. CFSR atmospheric, oceanic, and land surface output products are available at an hourly time resolution and a horizontal resolution of 0.5° latitude × 0.5° longitude. The CFSR data will be distributed by the National Climatic Data Center (NCDC) and NCAR. This reanalysis will serve many purposes, including providing the basis for most of the NCEP Climate Prediction Center's operational climate products by defining the mean states of the atmosphere, ocean, land surface, and sea ice over the next 30-yr climate normal (1981–2010); providing initial conditions for historical forecasts that are required to calibrate operational NCEP climate forecasts (from week 2 to 9 months); and providing estimates and diagnoses of the Earth's climate state over the satellite data period for community climate research. Preliminary analysis of the CFSR output indicates a product that is far superior in most respects to the reanalysis of the mid-1990s. The previous NCEP–NCAR reanalyses have been among the most used NCEP products in history; there is every reason to believe the CFSR will supersede these older products both in scope and quality, because it is higher in time and space resolution, covers the atmosphere, ocean, sea ice, and land, and was executed in a coupled mode with a more modern data assimilation system and forecast model.

Background Antibiotics are commonly administered to hospitalized patients with infiltrates for possible bacterial pneumonia, often leading to unnecessary treatment and increasing the risk for resistance emergence. Therefore, we performed a study to determine if an enhanced antibiotic de-escalation practice could improve antibiotic utilization in mechanically ventilated patients with suspected pneumonia cared for in an academic closed intensive care unit (ICU). Methods This was a prospective cross-over trial comparing routine antibiotic management (RAM) and enhanced antimicrobial de-escalation (EAD) performed within two medical ICUs (total 34 beds) at Barnes-Jewish Hospital, an academic referral center. Patients in the EAD group had their antibiotic orders and microbiology results reviewed daily by a dedicated team comprised of a second-year critical care fellow, an ICU attending physician and an ICU pharmacist. Antibiotic de-escalation recommendations were made when appropriate based on microbiologic test results and clinical response to therapy. Results There were 283 patients evaluable, with suspected pneumonia requiring mechanical ventilation: 139 (49.1%) patients in the RAM group and 144 (50.9%) in the EAD group. Early treatment failure based on clinical deterioration occurred in 33 (23.7%) and 40 (27.8%) patients, respectively ( P  = 0.438). In the remaining patients, antimicrobial de-escalation occurred in 70 (66.0%) and 70 (67.3%), respectively ( P  = 0.845). There was no difference between groups in total antibiotic days ((median (interquartile range)) 7.0 days (4.0, 9.0) versus 7.0 days (4.0, 8.8) ( P  = 0.616)); hospital mortality (25.2% versus 35.4% ( P  = 0.061)); or hospital duration (12.0 days (6.0, 20.0) versus 11.0 days (6.0, 22.0) ( P  = 0.918). Conclusions The addition of an EAD program to a high-intensity daytime staffing model already practicing a high-level of antibiotic stewardship in an academic ICU was not associated with greater antibiotic de-escalation or a reduction in the overall duration of antibiotic therapy. Trial registration ClinicalTrials.gov, NCT02685930 . Registered on 26 January 2016.

In the last three decades, Clostridium difficile infection (CDI) has increased in incidence and severity in many countries worldwide. The increase in CDI incidence has been particularly apparent among surgical patients. Therefore, prevention of CDI and optimization of management in the surgical patient are paramount. An international multidisciplinary panel of experts from the World Society of Emergency Surgery (WSES) updated its guidelines for management of CDI in surgical patients according to the most recent available literature. The update includes recent changes introduced in the management of this infection.

Flow disturbances near tall forest edges are receiving significant attention in diverse disciplines including ecology, forest management, meteorology, and fluid mechanics. Current theories suggest that near a forest edge, when the flow originates from a forest into a large clearing, the flow retains its forest canopy turbulence structure at the exit point. Here, we propose that this framework is not sufficiently general for dense forested edges and suggest that the flow shares several attributes with backward-facing step (BFS) flow. Similar analogies, such as rotor-like circulations, have been proposed by a number of investigators, though the consequences of such circulations on the primary terms in the mean momentum balance at the forest clearing edge have rarely been studied in the field. Using an array of three triaxial sonic anemometers positioned to measure horizontal and vertical gradients of the velocity statistics near a forest edge, we show that the flow structure is more consistent with an intermittent recirculation pattern, rather than a continuous rotor, whose genesis resembles the BFS flow. We also show that the lateral velocity variance, $\\overline {v'^2 } $, is the moment that adjusts most slowly with downwind distance as the flow exits from the forest into the clearing. Surprisingly, the longitudinal and vertical velocity variances ($\\overline {u'^2 } $ and $\\overline {w'^2 } $) at the forest edge were comparable in magnitude to their respective values at the center of a large grass-covered forest clearing, suggesting rapid adjustment at the edge. Discussions on how the forest edge modifies the spectra and co-spectra of momentum fluxes, effective mixing length, and static pressure are also presented.

•The role of non-macrolide antibiotics in microbiologically culture negative critically ill patients presenting with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) has not been described•Short courses (≤ 3 days) of non-macrolide antibiotics in critically ill patients with AECOPD did not affect the primary composite endpoint of in-hospital mortality, progression of ventilation, and readmission for AECOPD within 30 days•Short courses of non-macrolide antibiotics in critically ill patients with AECOPD did not affect incidence of adverse drug events•Additional studies exploring the role of shorter courses of non-macrolide antibiotics in critically ill patients with AECOPD are warranted In critically ill patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and without positive microbiological data, the efficacy and tolerability of short-course nonmacrolide antibiotics are ill-described and have pertinent implications in antimicrobial stewardship. This study compared the efficacy and tolerability of nonmacrolide antibiotic strategies in critically ill patients with AECOPD and without pertinent positive microbiological testing. This single-center, retrospective cohort study was conducted in culture-negative critically ill adults admitted to an intensive care unit (ICU) between July 1, 2014, and July 1, 2019, for the treatment of AECOPD. Included patients received treatment with an empiric corticosteroid, azithromycin, and/or a nonmacrolide antibiotic. Patients treated with a nonmacrolide antibiotic for ≤3 and >3 days made up the short- and standard-course groups, respectively. The prevalence of in-hospital mortality, progression to the need for ventilation, and/or readmission for AECOPD within 30 days (primary composite end point) was compared between the two groups. Additional end points included hospital and ICU lengths of stay (LOS), all-cause 30-day readmission, and prevalence of antibiotic-related adverse events. A total of 135 patients were included (short course, 66; standard course, 69). The differences in the primary composite end point (short vs standard, 24.2% vs 39.1%; P = 0.06) and its individual components were not significant. The median ICU LOS (2 vs 3 days) and hospital LOS (4 vs 6 days) were shorter in the short-course group (both, P < 0.01). Multivariate logistic regression confirmed no association between group assignment and the primary end point. Short-course nonmacrolide therapy in patients with AECOPD and no positive microbiological testing was not associated with differences in mortality, progression to ventilation, readmission rate, or prevalence of adverse drug events. Larger-scale prospective studies are needed to validate these findings.

Current data suggest potential benefits with β-lactam plus macrolide combination therapy for empiric treatment of intensive care unit (ICU) patients with severe community-acquired pneumonia (CAP). However, it is unclear whether deescalation to β-lactam monotherapy in the absence of positive results on diagnostic tests, such as the BioFire FilmArray Respiratory Panel 2 (BioFire polymerase chain reaction [PCR]), affects clinical outcomes. The purpose of this study was to compare outcomes between patients with negative BioFire PCR results deescalated to β-lactam monotherapy with those not deescalated. This single-center, retrospective cohort study assessed the in-hospital mortality rates of critically ill adults with CAP treated for ≥48 h with combination β-lactam and azithromycin therapy. Additional end points included hospital length of stay (LOS), ICU LOS, duration of mechanical ventilatory support, 30-day readmission, and incidence of azithromycin-related adverse effects. A total of 94 patients were included: 53 in the deescalation group and 41 in the nondeescalation group. No difference was observed with respect to in-hospital mortality (2.4% vs 11.3%, P = 0.312), although patients in the deescalated group experienced shorter ICU (1.9 vs 3.4 days, P = 0.029) and hospital LOS (6 vs 7 days, P = 0.025). No differences were found between groups with respect to additional secondary end points. Simple logistic regression confirmed that deescalation was not associated with hospital mortality (odds ratio = 0.17, 95% CI, 0.02–1.70). In this study of ICU patients with severe CAP and a negative BioFire PCR result, deescalation from combination β-lactam and macrolide therapy to β-lactam monotherapy was not associated with increased in-hospital mortality but was associated with decreased hospital and ICU LOS. Larger prospective studies are warranted to verify these findings.

A family of interferon (IFN) regulatory factors (IRFs) have been shown to play role in transcription of IFN genes as well as IFN-stimulated genes. We report the identification of a member of the IRF family which we have named IRF-3. The IRF-3 gene is present in a single copy in human genomic DNA. It is expressed constitutively in a variety of tissues and no increase in the relative steady-state levels of IRF-3 mRNA was observed in virus-infected or IFN-treated cells. The IRF-3 gene encodes a 50-kDa protein that binds specifically to the IFN-stimulated response element (ISRE) but not to the IRF-1 binding site PRD-I. Overexpression of IRF-3 stimulates expression of the IFN-stimulated gene 15 (ISG15) promoter, an ISRE-containing promoter. The murine IFNA4 promoter, which can be induced by IRF-1 or viral infection, is not induced by IRF-3. Expression of IRF-3 as a Gal4 fusion protein does not activate expression of a chloramphenicol acetyltransferase reporter gene containing repeats of the Gal4 binding sites, indicating that this protein does not contain the transcription transactivation domain. The high amino acid homology between IRF-3 and ISG factor 3 γ polypeptide (ISGF3γ) and their similar binding properties indicate that, like ISGF3γ, IRF-3 may activate transcription by complex formation with other transcriptional factors, possibly members of the Stat family. Identification of this ISRE-binding protein may help us to understand the specificity in the various Stat pathways.

Expression of ErbB2 protein is inversely correlated with the prognosis in cancer patients. Consequently, strategies targeting ErbB2 remain an attractive option in treating several types of malignancies, including oral cancer. In addition, many studies have shown that emodin and emodin derivatives are able to inhibit growth of ErbB2-overexpressing tumor cells. In this study, a series of computer modeling-generated emodin analogues were synthesized and tested for their antiproliferative activity against oral cancer cell lines overexpressing ErbB2. Among these analogues, em08red (1,8-dihydroxy-9(10H)-anthracenone) demonstrated potent antiproliferative activity against all three tested ErbB2-overexpressing cell lines, ie, FaDu, HSC3, and OECM1. Treatment with em08red significantly downregulated activation of ErbB2 as well as the ErbB2 protein expression level in the tested cell lines and induced G2 arrest. Antiapoptosis protein (Bcl-xl and Bcl-2) expression levels were also downregulated, and active caspase-3 and caspase-9 was detected in cells after treatment with em08red. Moreover, treatment with em08red stimulated production of cytotoxic reactive oxygen species in treated cells, and this could be partially reversed by pretreatment with N-acetylcysteine. Overall, we demonstrated inhibition of ErbB2 function and induction of reactive oxygen species in tumor cells by em08red, which prevented proliferation of tumor cells and induced apoptotic cell death.