Nephrotoxicity During Vancomycin Therapy in Combination with Piperacillin-Tazobactam or Cefepime

Recent reports have demonstrated that vancomycin (VAN) may lead to an increase in the incidence of acute kidney injury (AKI) when it is combined with antipseudomonal beta-lactams. This study compared the incidence of AKI associated with VAN plus piperacillin-tazobactam (TZP) or cefepime (FEP). This was a retrospective, matched cohort study that was conducted at an academic medical center between September 2010 and September 2014 and that included adult patients without severe chronic or structural kidney disease, dialysis, pregnancy, cystic fibrosis, or a hospital transfer receiving TZP-VAN or FEP-VAN for at least 48 h. The primary outcome was the difference in the AKI incidence between the TZP-VAN and FEP-VAN groups, evaluated using the risk, injury, failure, loss of kidney function, and end-stage kidney disease (RIFLE) criteria. Patients in the two groups were matched on the basis of age, sex, severity of illness, baseline creatinine clearance, hypotension, number of nephrotoxicity risk factors, and intravenous contrast exposure. In total, 4,193 patients met all inclusion criteria (3,605 received TZP-VAN and 588 received FEP-VAN). The unadjusted AKI incidence was 21.4% in patients receiving TZP-VAN, whereas it was 12.6% in patients receiving FEP-VAN (P \u3c 0.001). After the patients were matched, 1,633 patients receiving TZP-VAN and 578 patients receiving FEP-VAN were evaluated. The AKI incidence remained higher in patients receiving TZP-VAN than in those receiving FEP-VAN (21.4% versus 12.5%, P \u3c 0.0001). This trend remained true for all classifications of the RIFLE criteria. After controlling for remaining confounders, TZP-VAN therapy was associated with 2.18 times the odds of AKI than FEP-VAN therapy (95% confidence interval, 1.64 to 2.94 times) in logistic regression. AKI was significantly more common in patients receiving vancomycin in combination with piperacillin-tazobactam than in those receiving vancomycin in combination with cefepime. This finding reinforces the need for the judicious use of combination empirical antimicrobial therapy

A pushing mechanism for microtubule aster positioning in a large cell type

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Meaders, J. L., de Matos, S. N., & Burgess, D. R. A pushing mechanism for microtubule aster positioning in a large cell type. Cell Reports, 33(1), (2020): 108213, doi:10.1016/j.celrep.2020.108213.After fertilization, microtubule (MT) sperm asters undergo long-range migration to accurately position pronuclei. Due to the large sizes of zygotes, the forces driving aster migration are considered to be from pulling on the astral MTs by dynein, with no significant contribution from pushing forces. Here, we re-investigate the forces responsible for sperm aster centration in sea urchin zygotes. Our quantifications of aster geometry and MT density preclude a pulling mechanism. Manipulation of aster radial lengths and growth rates, combined with quantitative tracking of aster migration dynamics, indicates that aster migration is equal to the length of rear aster radii, supporting a pushing model for centration. We find that dynein inhibition causes an increase in aster migration rates. Finally, ablation of rear astral MTs halts migration, whereas front and side ablations do not. Collectively, our data indicate that a pushing mechanism can drive the migration of asters in a large cell type.We would like to thank Dr. Jesse Gatlin for sending us the Tau-mCherry fusion protein for imaging live MTs. We would also like to thank Dr. Timothy Mitchison, Dr. Christine Field, and Dr. James Pelletier for supplying us with CA4, p150-CC1, and EB1-GFP peptides, as well as for fruitful discussions. Finally, we would like to thank Dr. Charles Shuster and Leslie Toledo-Jacobo for constructive feedback when preparing the manuscript. We thank Bret Judson and the Boston College Imaging Core for infrastructure and support. This material is based upon work supported by NSF grant no. 124425 to D.R.B

Multiple Inflation, Cosmic String Networks and the String Landscape

Motivated by the string landscape we examine scenarios for which inflation is a two-step process, with a comparatively short inflationary epoch near the string scale and a longer period at a much lower energy (like the TeV scale). We quantify the number of $e$-foldings of inflation which are required to yield successful inflation within this picture. The constraints are very sensitive to the equation of state during the epoch between the two inflationary periods, as the extra-horizon modes can come back inside the horizon and become reprocessed. We find that the number of $e$-foldings during the first inflationary epoch can be as small as 12, but only if the inter-inflationary period is dominated by a network of cosmic strings (such as might be produced if the initial inflationary period is due to the brane-antibrane mechanism). In this case a further 20 $e$-foldings of inflation would be required at lower energies to solve the late universe's flatness and horizon problems.Comment: 27 pages, 6 figures; v2: refences adde

Compositions, Methods And Kits Relating To Thrombin Degradation Resistant Fibroblast Growth Factor-1

The invention relates to novel degradation resistant FGF-1, and methods for producing and using the same. More specifically, the invention relates to identification of a thrombin degradation resistant FGF-1, an a nucleic acid encoding the same. The thrombin degradation resistant FGF-1 can elicit responses that are otherwise typically impeded by degradation of FGF-1 by thrombin. Thrombin degradation resistant FGF-1 is an important molecule for effecting an FGF-1 response that would be otherwise inhibited by thrombin. Thus, the present invention provides a powerful therapeutic for diseases or disorders wherein an FGF-1 response can mediate a reduction in the frequency or intensity of a symptom of the disease or disorder but for degradation of FGF-1 before it can effect the response

The effect of Psoroptes ovis infestation on ovine epidermal barrier function

Sheep scab is an intensively pruritic, exudative and allergic dermatitis of sheep caused by the ectoparasitic mite Psoroptes ovis. The purpose of the present study was to investigate the effect of P. ovis infestation on different components of the ovine epidermal barrier within the first 24 hours post-infestation (hpi). To achieve this, the expression of epidermal differentiation complex (EDC) genes and epidermal barrier proteins, the nature and severity of epidermal pathology and transepidermal water loss (TEWL) were evaluated. By 1 hpi a significant dermal polymorphonuclear infiltrate and a significant increase in TEWL with maximal mean TEWL (598.67 g/m(2)h) were observed. Epidermal pathology involving intra-epidermal pustulation, loss of epidermal architecture and damage to the basement membrane was seen by 3 hpi. Filaggrin and loricrin protein levels in the stratum corneum declined significantly in the first 24 hpi and qPCR validation confirmed the decrease in expression of the key EDC genes involucrin, filaggrin and loricrin observed by microarray analysis, with 5.8-fold, 4.5-fold and 80-fold decreases, respectively by 24 hpi. The present study has demonstrated that early P. ovis infestation disrupts the ovine epidermal barrier causing significant alterations in the expression of critical barrier components, epidermal pathology, and TEWL. Many of these features have also been documented in human and canine atopic dermatitis suggesting that sheep scab may provide a model for the elucidation of events occurring in the early phases of atopic sensitisation

Inhibition of glycolysis and mitochondrial respiration promotes radiosensitisation of neuroblastoma and glioma cells

Background: Neuroblastoma accounts for 7% of paediatric malignancies but is responsible for 15% of all childhood cancer deaths. Despite rigorous treatment involving chemotherapy, surgery, radiotherapy and immunotherapy, the 5-year overall survival rate of high-risk disease remains < 40%, highlighting the need for improved therapy. Since neuroblastoma cells exhibit aberrant metabolism, we determined whether their sensitivity to radiotherapy could be enhanced by drugs affecting cancer cell metabolism. Methods: Using a panel of neuroblastoma and glioma cells, we determined the radiosensitising effects of inhibitors of glycolysis (2-DG) and mitochondrial function (metformin). Mechanisms underlying radiosensitisation were determined by metabolomic and bioenergetic profiling, flow cytometry and live cell imaging and by evaluating different treatment schedules. Results: The radiosensitising effects of 2-DG were greatly enhanced by combination with the antidiabetic biguanide, metformin. Metabolomic analysis and cellular bioenergetic profiling revealed this combination to elicit severe disruption of key glycolytic and mitochondrial metabolites, causing significant reductions in ATP generation and enhancing radiosensitivity. Combination treatment induced G2/M arrest that persisted for at least 24 h post-irradiation, promoting apoptotic cell death in a large proportion of cells. Conclusion: Our findings demonstrate that the radiosensitising effect of 2-DG was significantly enhanced by its combination with metformin. This clearly demonstrates that dual metabolic targeting has potential to improve clinical outcomes in children with high-risk neuroblastoma by overcoming radioresistance

An Observed Correlation Between Thermal and Non-Thermal Emission in Gamma-Ray Bursts

Recent observations by the $Fermi$ Gamma-ray Space Telescope have confirmed the existence of thermal and non-thermal components in the prompt photon spectra of some Gamma-ray bursts (GRBs). Through an analysis of six bright Fermi GRBs, we have discovered a correlation between the observed photospheric and non-thermal $\gamma$-ray emission components of several GRBs using a physical model that has previously been shown to be a good fit to the Fermi data. From the spectral parameters of these fits we find that the characteristic energies, $E_{\rm p}$ and $kT$, of these two components are correlated via the relation $E_{\rm p} \propto T^{\alpha}$ which varies from GRB to GRB. We present an interpretation in which the value of index $\alpha$ indicates whether the jet is dominated by kinetic or magnetic energy. To date, this jet composition parameter has been assumed in the modeling of GRB outflows rather than derived from the data

Efficacy and Safety of Vancomycin Loading Doses in Critically Ill Patients with Methicillin-Resistant \u3ci\u3eStaphylococcus aureus\u3c/i\u3e Infection

Background: While vancomycin loading doses may facilitate earlier pharmacokinetic–pharmacodynamic target attainment, the impact of loading doses on clinical outcomes remains understudied. Critically ill patients are at highest risk of morbidity and mortality from methicillin resistant Staphylococcus aureus (MRSA) infection and hypothesized to most likely benefit from a loading dose. We sought to determine the association between receipt of a vancomycin loading dose and clinical outcomes in a cohort of critically ill adults. Methods: Four hundred and forty-nine critically ill patients with MRSA cultures isolated from blood or respiratory specimens were eligible for the study. Cohorts were established by receipt of a loading dose (⩾20 mg/kg actual body weight) or not. The primary outcome was clinical failure, a composite outcome of death within 30 days of first MRSA culture, blood cultures positive ⩾7 days, white blood cell count up to 5 days from vancomycin initiation, temperature up to 5 days from vancomycin initiation, or substitution (or addition) of another MRSA agent. Results: There was no difference in the percentage of patients experiencing clinical failure between the loading dose and no loading dose groups (74.8% versus 72.8%; p = 0.698). Secondary outcomes were also similar between groups, including mortality and acute kidney injury, as was subgroup analysis based on site of infection. Exploratory analyses, including assessment of loading dose based on quartiles and a multivariable logistic regression model showed no differences. Conclusion: Use of vancomycin loading doses was not associated with improved clinical outcomes in critically ill patients with MRSA infection