Central line-associated bloodstream infections (CLABSIs) are associated with increased mortality, hospital length of stay, and cost. Antimicrobial treatment guidelines for CLABSIs are primarily based ...on expert opinion. We hypothesized that shorter antimicrobial treatment duration is associated with decreased 60-day recurrence-free survival.
A retrospective cohort study of all adults with hospital-acquired CLABSIs (HA-CLABSIs) over 5 years at a single tertiary care academic hospital was performed. The time from the end of effective antimicrobial treatment until recurrence of infection or mortality, censored at 60 days after the end of antimicrobial treatment, represented the primary outcome. Effective antimicrobial treatment was defined as the administration of at least one antimicrobial to which the causative organism was sensitive.
A total of 366 cases met eligibility criteria. The median Sequential Organ Failure Assessment (SOFA) score was 6 (interquartile range (IQR) 4-8). Patients were treated for a median of 15 (IQR 10-20) days with effective antimicrobials. The incidence of 60-day mortality or recurrence after completion of the antimicrobial course was 22.1% (81 patients). In a Cox proportional-hazards model, antimicrobial treatment duration (hazard ratio (HR) = 0.35; 95% confidence interval (CI) 0.26-0.48), SOFA score (HR = 1.16; 95% CI 1.09-1.22), and age (HR = 1.021; 95% CI = 1.004-1.037) were associated with mortality or recurrence. The effect of antimicrobial treatment duration appeared to plateau after 15 days.
Longer antimicrobial treatment duration in patients with HA-CLABSIs is associated with improved recurrence-free survival during the first 60 days after infection. This effect appears to plateau after 15 days of treatment. Prospective studies are needed to definitively determine the optimal antimicrobial treatment duration for CLABSIs.
Soluble methane monooxygenase (sMMO) facilitates the conversion of methane to methanol at a non-heme Fe
IV
2
intermediate MMOH
Q
, which is formed in the active site of the sMMO hydroxylase component ...(MMOH) during the catalytic cycle. Other biological systems also employ high-valent Fe
IV
sites in catalysis; however, MMOH
Q
is unique as Nature’s only identified Fe
IV
2
intermediate. Previous
57
Fe Mössbauer spectroscopic studies have shown that MMOH
Q
employs antiferromagnetic coupling of the two Fe
IV
sites to yield a diamagnetic cluster. Unfortunately, this lack of net spin prevents the determination of the local spin state (
S
loc
) of each of the irons by most spectroscopic techniques. Here, we use Fe Kβ X-ray emission spectroscopy (XES) to characterize the local spin states of the key intermediates of the sMMO catalytic cycle, including MMOH
Q
trapped by rapid-freeze-quench techniques. A pure XES spectrum of MMOH
Q
is obtained by subtraction of the contributions from other reaction cycle intermediates with the aid of Mössbauer quantification. Comparisons of the MMOH
Q
spectrum with those of known
S
loc
= 1 and
S
loc
= 2 Fe
IV
sites in chemical and biological models reveal that MMOH
Q
possesses
S
loc
= 2 iron sites. This experimental determination of the local spin state will help guide future computational and mechanistic studies of sMMO catalysis.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
IMPORTANCE: Cefepime and piperacillin-tazobactam are commonly administered to hospitalized adults for empirical treatment of infection. Although piperacillin-tazobactam has been hypothesized to cause ...acute kidney injury and cefepime has been hypothesized to cause neurological dysfunction, their comparative safety has not been evaluated in a randomized clinical trial. OBJECTIVE: To determine whether the choice between cefepime and piperacillin-tazobactam affects the risks of acute kidney injury or neurological dysfunction. DESIGN, SETTING, AND PARTICIPANTS: The Antibiotic Choice on Renal Outcomes (ACORN) randomized clinical trial compared cefepime vs piperacillin-tazobactam in adults for whom a clinician initiated an order for antipseudomonal antibiotics within 12 hours of presentation to the hospital in the emergency department or medical intensive care unit at an academic medical center in the US between November 10, 2021, and October 7, 2022. The final date of follow-up was November 4, 2022. INTERVENTIONS: Patients were randomized in a 1:1 ratio to cefepime or piperacillin-tazobactam. MAIN OUTCOMES AND MEASURES: The primary outcome was the highest stage of acute kidney injury or death by day 14, measured on a 5-level ordinal scale ranging from no acute kidney injury to death. The 2 secondary outcomes were the incidence of major adverse kidney events at day 14 and the number of days alive and free of delirium and coma within 14 days. RESULTS: There were 2511 patients included in the primary analysis (median age, 58 years IQR, 43-69 years; 42.7% were female; 16.3% were Non-Hispanic Black; 5.4% were Hispanic; 94.7% were enrolled in the emergency department; and 77.2% were receiving vancomycin at enrollment). The highest stage of acute kidney injury or death was not significantly different between the cefepime group and the piperacillin-tazobactam group; there were 85 patients (n = 1214; 7.0%) in the cefepime group with stage 3 acute kidney injury and 92 (7.6%) who died vs 97 patients (n = 1297; 7.5%) in the piperacillin-tazobactam group with stage 3 acute kidney injury and 78 (6.0%) who died (odds ratio, 0.95 95% CI, 0.80 to 1.13, P = .56). The incidence of major adverse kidney events at day 14 did not differ between groups (124 patients 10.2% in the cefepime group vs 114 patients 8.8% in the piperacillin-tazobactam group; absolute difference, 1.4% 95% CI, −1.0% to 3.8%). Patients in the cefepime group experienced fewer days alive and free of delirium and coma within 14 days (mean SD, 11.9 4.6 days vs 12.2 4.3 days in the piperacillin-tazobactam group; odds ratio, 0.79 95% CI, 0.65 to 0.95). CONCLUSIONS AND RELEVANCE: Among hospitalized adults in this randomized clinical trial, treatment with piperacillin-tazobactam did not increase the incidence of acute kidney injury or death. Treatment with cefepime resulted in more neurological dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05094154
There is a need to individualize assays for tumor molecular phenotyping, given variations in the differentiation status of tumor and normal tissues in different patients. To address this, we ...performed single-cell genomics of breast tumors and adjacent normal cells propagated for a short duration under growth conditions that enable epithelial reprogramming. Cells analyzed were either unselected for a specific subpopulation or phenotypically defined as undifferentiated and highly clonogenic ALDH
/CD49f
/EpCAM
luminal progenitors, which express both basal cell and luminal cell-enriched genes. We analyzed 420 tumor cells and 284 adjacent normal cells for expression of 93 genes that included a PAM50-intrinsic subtype classifier and stemness-related genes. ALDH
/CD49f
/EpCAM
tumor and normal cells clustered differently compared with unselected tumor and normal cells. PAM50 gene-set analyses of ALDH
/CD49f
/EpCAM
populations efficiently identified major and minor clones of tumor cells, with the major clone resembling clinical parameters of the tumor. Similarly, a stemness-associated gene set identified clones with divergent stemness pathway activation within the same tumor. This refined expression profiling technique distinguished genes truly deregulated in cancer from genes that identify cellular precursors of tumors. Collectively, the assays presented here enable more precise identification of cancer-deregulated genes, allow for early identification of therapeutically targetable tumor cell subpopulations, and ultimately provide a refinement of precision therapeutics for cancer treatment.
.
Abstract
Background
Cefepime and piperacillin-tazobactam are commonly administered to hospitalized adults for empiric treatment of infection. Although piperacillin-tazobactam has been hypothesized to ...cause acute kidney injury and cefepime has been hypothesized to cause neurological dysfunction, their comparative safety has never been evaluated in a randomized trial. We aimed to determine whether choice between piperacillin-tazobactam and cefepime affects risks of acute kidney injury or neurological dysfunction.
Methods
The Antibiotic Choice On ReNal outcomes (ACORN) study was a pragmatic randomized trial comparing piperacillin-tazobactam versus cefepime, conducted from November 2021 to October 2022; patient follow up concluded on November 4, 2022. Eligible patients were adults in the emergency department or medical intensive care unit for whom a clinician initiated anti-pseudomonal antibiotics within 12 hours of presentation to the hospital. Patients were randomized in a 1:1 ratio to cefepime or piperacillin-tazobactam. The primary outcome was the highest stage of acute kidney injury or death by day 14, measured on a 5-level ordinal scale ranging from no acute kidney injury to death. The two secondary outcomes were the incidence of major adverse kidney events at day 14 and number of days alive and free of delirium and coma within 14 days.
Results
Among the 2,511 patients in the primary analysis (median age, 58 years; 42.7% female; 94.7% enrolled in the emergency department, 77.2% receiving vancomycin at enrollment), the highest stage of acute kidney injury or death did not differ between the cefepime and piperacillin-tazobactam groups (odds ratio OR, 0.95; 95% confidence interval CI, 0.80 to 1.13; P = 0.56). The incidence of major adverse kidney events at day 14 did not differ between groups (OR, 1.18; 95%CI, 0.90 to 1.54). Patients in the cefepime group experienced fewer days alive and free of delirium and coma within 14 days (OR, 0.79; 95%CI, 0.65 to 0.95).Figure 1.Flow of participants through the trial.Figure 2.Antibiotic receipt by group
For the cefepime group (left) and piperacillin-tazobactam group (right), the percentage of patients who received cefepime (solid red) and piperacillin-tazobactam (dashed blue) is displayed on each day from enrollment through day 7. The denominator for each study day is the total number of patients who remain in the hospital.Figure 3:Effect Modification of the Primary and Secondary Outcomes.
For each subgroup, the effect of cefepime vs piperacillin-tazobactam is shown for the primary outcome of highest stage of acute kidney injury (AKI) or death and the secondary outcomes of major adverse kidney events at 14 days (MAKE14) and the number of days alive and free of delirium and coma within14 days. For the renal outcomes, odds ratios less than 1.0 indicate a better outcome in the cefepime group compared to the piperacillin-tazobactam group. For the outcome days alive and free of delirium and coma, an odds ratio greater than 1.0 indicates a better outcome in the cefepime group compared to the piperacillin-tazobactam group. Baseline Coma was added post hoc. KRT is kidney replacement therapy.
Conclusion
Among hospitalized adults in this randomized trial, treatment with piperacillin-tazobactam did not increase the incidence of acute kidney injury or death. Treatment with cefepime resulted in more neurological dysfunction
Disclosures
Jonathan Casey, MD. MSc, Fisher and Paykel: Travel grant Jesse Wrenn, MD, PhD, Bristol Myers Squibb: Grant/Research Support Matthew Semler, MD, MSc, Baxter International: Advisor/Consultant Todd Rice, MD, MSc, Cumberland Pharmaceuticals: Advisor/Consultant|Cytovale Inc: Advisor/Consultant|Sanofi: Advisor/Consultant
U ovom ćemo članku raspravljati o metodama tumačenja koje pomažu da vam evanđelja i novozavjetne poslanice budu jasne i smislene. Naša svrha nije ulaziti u tehničku raspravu novozavjetnih ...znanstvenika o ovim knjigama, iako ćemo se povremeno pozivati na ove rasprave u svrhu daljnjeg pojašnjenja. Naš je cilj pomoći čitatelju da vidi na koji način pažljivo, promišljeno čitanje evanđelja i poslanica uz molitvu može biti nagrađeno smislenim uvidima te može donijeti duhovnu obnovu.
The biomagnification of polychlorinated biphenyls (PCB), toxaphene, and the DDT family of metabolites was investigated in the epibenthic Mysis relicta (mysid), the benthic Pontoporeia hoyi ...(amphipod), plankton, particulate flux, surficial sediments, and Myoxocephalus thompsoni (deepwater sculpin) in southeastern Lake Michigan. DDE was the most strongly biomagnified compound, increasing 28.7 times in average concentration from plankton to fish. PCB increased 12.9 times in average concentration from plankton to fish while toxaphene increased by an average factor of 4.7. Particle flux was comprised of lower chlorinated PCB homologues (average chlorine number = 3.8) than the biota (4.5-5.0) and sediments (4.6), possibly reflecting strong influences from atmospheric deposition and/or zooplankton egestion. The percent of higher chlorinated PCB homologues (5 and 6 chlorine atoms per PCB molecule) increased from 54-56% of the total PCB in plankton and M. relicta, to 61% in P. hoyi, to 74% in sculpins. Amphipods contained greater concentrations than mysids of PCB, DDT residues, and toxaphene, possibly reflecting differences in habitat (benthic vs epibenthic) and diet (detritus vs plankton). Based on estimates of average areal biomass and contaminant concentration, offshore Lake Michigan P. hoyi populations contain approximately 15.0 times as much toxaphene, 9.5 times as much total DDT, and 12.0 times as much PCB as the offshore M. relicta populations. Thus, amphipods may represent a greater reservoir than mysids for contaminant storage and subsequent recycling in offshore Lake Michigan.
Myeloablative and immunoablative therapy followed by autologous hematopoietic stem cell transplantation (AHSCT) has been shown to be effective in patients with highly active relapsing multiple ...sclerosis (RMS) with continued activity despite treatment with approved disease-modifying therapies (DMTs). However, AHSCT has not been formally compared to the contemporary high efficacy biologic DMTs in a clinical trial.
To implement a trial to compare efficacy, safety, and cost-effectiveness of AHSCT to best available medical therapy (BAT) in treatment-resistant RMS.
The BEAT-MS trial was developed by a collaborative study team including academic neurology and transplant protocol chairs, a health economist, neuroradiologist and patient-reported outcome measure expert. The trial will be conducted by the Immune Tolerance Network (ITN) in collaboration with the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), and sponsored by the National Institute of Allergy and Infectious Diseases (UM1AI109565). The trial will be conducted at 18 paired MS and transplant centers in the United States and 1 in the United Kingdom.
BEAT-MS will be a multi-center prospective rater-blinded randomized controlled trial of 156 participants comparing AHSCT versus BAT. Participants with highly active treatment-resistant relapsing MS and mild to moderate disability will be randomized at a 1:1 ratio. Eligible participants will be age 18-55. Co-morbid medical conditions that increase the risk of AHSCT will be excluded. For participants randomized to the AHSCT arm, peripheral blood stem cells (PBSC) will be mobilized with cyclophosphamide, dexamethasone, and filgrastim, collected by leukapheresis, and cryopreserved. Participants will receive conditioning with carmustine, etoposide, cytarabine, and melphalan (BEAM) and rabbit anti-thymocyte globulin prior to re-infusion of the unmanipulated autologous PBSC. Participants randomized to the BAT arm will be treated with either natalizumab, alemtuzumab, ocrelizumab, or rituximab. All participants will be followed for 72 months. The primary endpoint will be MS relapse-free survival. The primary statistical analysis will be performed when all randomized participants active in the study have completed the Month 36 evaluation. Secondary and exploratory endpoints will compare MS disease activity assessed clinically and by magnetic resonance imaging, and include neurodegeneration, safety outcomes, quality of life, cost-effectiveness, and immune signatures.
BEAT-MS will be a large scale prospective multi-center randomized clinical trial comparing AHSCT to contemporary high efficacy DMTs, with the goal of determining whether AHSCT is an appropriate treatment option for patients with highly active RMS for whom BAT would be prescribed in current clinical neurology practice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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