Towards Precision Medicine: Therapeutic Drug Monitoring–Guided Dosing of Vancomycin and β-lactam Antibiotics to Maximize Effectiveness and Minimize Toxicity

Purpose The goal of this review is to explore the role of antimicrobial therapeutic drug monitoring (TDM), especially in critically ill, obese, and older adults, with a specific focus on β-lactams and vancomycin. Summary The continued rise of antimicrobial resistance prompts the need to optimize antimicrobial dosing. The aim of TDM is to individualize antimicrobial dosing to achieve antibiotic exposures associated with improved patient outcomes. Initially, TDM was developed to minimize adverse effects during use of narrow therapeutic index agents. Today, patient and organism complexity are expanding the need for precision dosing through TDM services. Alterations of pharmacokinetics and pharmacodynamics (PK/PD) in the critically ill, obese, and older adult populations, in conjunction with declining organism susceptibility, complicate attainment of therapeutic targets. Over the last decade, antimicrobial TDM has expanded with the emergence of literature supporting β-lactam TDM and a shift from monitoring vancomycin trough concentrations to monitoring of the ratio of area under the concentration (AUC) curve to minimum inhibitory concentration (MIC). PK/PD experts should be at the forefront of implementing precision dosing practices. Conclusion Precision dosing through TDM is expanding and is especially important in populations with altered PK/PD, including critically ill, obese, and older adults. Due to wide PK/PD variability in these populations, TDM is vital to maximize antimicrobial effectiveness and decrease adverse event rates. However, there is still a need for studies connecting TDM to patient outcomes. Providing patient-specific care through β-lactam TDM and transitioning to vancomycin AUC/MIC monitoring may be challenging, but with experts at the forefront of this initiative, PK-based optimization of antimicrobial therapy can be achieved

Factors associated with D-dimer levels in HIV-infected individuals.

BACKGROUND: Higher plasma D-dimer levels are strong predictors of mortality in HIV+ individuals. The factors associated with D-dimer levels during HIV infection, however, remain poorly understood. METHODS: In this cross-sectional study, participants in three randomized controlled trials with measured D-dimer levels were included (N = 9,848). Factors associated with D-dimer were identified by linear regression. Covariates investigated were: age, gender, race, body mass index, nadir and baseline CD4+ count, plasma HIV RNA levels, markers of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6]), antiretroviral therapy (ART) use, ART regimens, co-morbidities (hepatitis B/C, diabetes mellitus, prior cardiovascular disease), smoking, renal function (estimated glomerular filtration rate [eGFR] and cystatin C) and cholesterol. RESULTS: Women from all age groups had higher D-dimer levels than men, though a steeper increase of D-dimer with age occurred in men. Hepatitis B/C co-infection was the only co-morbidity associated with higher D-dimer levels. In this subgroup, the degree of hepatic fibrosis, as demonstrated by higher hyaluronic acid levels, but not viral load of hepatitis viruses, was positively correlated with D-dimer. Other factors independently associated with higher D-dimer levels were black race, higher plasma HIV RNA levels, being off ART at baseline, and increased levels of CRP, IL-6 and cystatin C. In contrast, higher baseline CD4+ counts and higher high-density lipoprotein cholesterol were negatively correlated with D-dimer levels. CONCLUSIONS: D-dimer levels increase with age in HIV+ men, but are already elevated in women at an early age due to reasons other than a higher burden of concomitant diseases. In hepatitis B/C co-infected individuals, hepatic fibrosis, but not hepatitis viral load, was associated with higher D-dimer levels

System design study of a VLEO satellite platform using the IRS RF helicon-based plasma thruster

To achieve a feasible lifetime of several years, most satellites are deployed in orbits higher than 400 km. Drag of residual atmosphere causes a slow orbit decay, resulting in the deorbit of the spacecraft. However, e.g. optical instruments or communication devices would significantly benefit from lower altitudes in the range of 150–250 km. A solution to achieve this could be the application of atmosphere-breathing electric propulsion (ABEP), where the residual atmosphere is used to generate continuous thrust that compensates the drag.Within the EU-funded DISCOVERER project, the Institute of Space Systems (IRS) developed an electrode-less RF Helicon-based Plasma Thruster (IPT) suitable for such applications. Ignition and preliminary discharge characterizations of the IPT have been carried out at IRS facilities, using argon, nitrogen and oxygen. To further characterize the plasma plume, a torsional pendulum has been designed to determine the (local) momentum flux in the plasma jet, as well as a three-axis magnetic B-dot probe to carry out time-varying magnetic field measurements. Various intake designs were investigated, opening the possibility to conduct studies on potential satellite platforms within the frame of the ESA-funded project RAM-CLEP.A design study for an Earth Observation and Telecommunication satellite operating at 150–250 km with an extended mission lifetime is currently being carried out. The first system assessment focused on the comparison of different spacecraft configurations (“slender body” and “flat body”) and intake designs (specular or diffuse) with regard to overall drag and ABEP performance requirements.In this contribution, the design approaches for the current thruster and the diagnostic methods are depicted. Moreover, the current status of the system assessment is presented. Upcoming experimental studies of the ABEP system e.g. within the ESA-project RAM-CLEP and additional activities planned on system assessment are outlined.<br/

Factors Associated with D-Dimer Levels in HIV-Infected Individuals

Matti A Ristola on työryhmän jäsen.Peer reviewe

The Grizzly, September 25, 1981

Greaseband Tonight • Campus Welcome • Fridge Fee Unfrozen • Deutsch und Deutschland Heute: German Professor Co-authors Text • Public Speaking Exemption Exam • Books Sought by Ursinus Friends • Red Cross Bloodmobile at Helfferich Hall • Career Planning and Placement Office • Dessert Held in Union • Fast Food Service Losing Convenience • ProTheatre: Canterbury Tales Presented • Transplanted Texan: Nobody Expects the Moral Majority • School Bands Looking for Musicians • WRUC: Back on the Air? • First Coffeehouse Sparkles With Talent • Late Mail for Off-Campus Houses • [Reprinted Articles About the Greaseband] • Bear\u27s Booters Kick Off Season • Business as Usual for Cross-Country • Bears Drop 10-3 Decision to Western Maryland • Davis Leads Hockey Over Widenerhttps://digitalcommons.ursinus.edu/grizzlynews/1061/thumbnail.jp

Hepatitis C virus (HCV) RNA profiles among chronic HIV/HCV-coinfected individuals in ESPRIT; spontaneous HCV RNA clearance observed in nine individuals.

OBJECTIVES: Studies have shown that hepatitis C virus (HCV) RNA levels remain stable over time in HIV/HCV-coinfected individuals taking combination antiretroviral therapy (cART), while spontaneous clearance of HCV RNA during the persistent infection phase has been documented only rarely among those with the CC interleukin (IL)-28B genotype. This study describes HCV RNA profiles and factors associated with changes over time in HCV RNA levels in the ESPRIT study. METHODS: HIV/HCV-coinfected individuals positive for HCV RNA were included in the study. Follow-up was counted from the first HCV RNA positive test and censored at the initiation of interferon-based treatment. HCV RNA and IL-28B measurements were performed in the same reference laboratory. Random effects mixed models were used to analyse changes over time in HCV RNA. RESULTS: A total of 312 ESPRIT patients were included in the study (151 in the arm receiving subcutaneous recombinant IL-2 and 161 in the control arm). Most of the patients were white (89%) and male (76%), and they had a median of 5 HCV RNA measurements per person [interquartile range (IQR) 3-6; range 1-9]. Median follow-up was 5 years (IQR: 2-6 years). At baseline, 96% of patients were taking cART and 93% had undetectable HIV RNA. Mean HCV RNA levels decreased by 13% per year over the study period [95% confidence interval (CI) 8-18%; P < 0.0001]. Baseline HCV RNA levels and the change over time in HCV RNA did not differ by randomization arm (P = 0.16 and P = 0.56, respectively). Nine individuals spontaneously cleared HCV RNA during follow-up [IL-28B genotypes: CC, five patients (56%); CT, four patients (44%)]. CONCLUSIONS: HCV RNA levels decreased over time in this population with well-controlled HIV infection. Spontaneous clearance of HCV RNA was documented in five individuals with IL-28B genotype CC and four with the CT genotype

Intercomparison of the northern hemisphere winter mid-latitude atmospheric variability of the IPCC models

We compare, for the overlapping time frame 1962-2000, the estimate of the northern hemisphere (NH) mid-latitude winter atmospheric variability within the XX century simulations of 17 global climate models (GCMs) included in the IPCC-4AR with the NCEP and ECMWF reanalyses. We compute the Hayashi spectra of the 500hPa geopotential height fields and introduce an integral measure of the variability observed in the NH on different spectral sub-domains. Only two high-resolution GCMs have a good agreement with reanalyses. Large biases, in most cases larger than 20%, are found between the wave climatologies of most GCMs and the reanalyses, with a relative span of around 50%. The travelling baroclinic waves are usually overestimated, while the planetary waves are usually underestimated, in agreement with previous studies performed on global weather forecasting models. When comparing the results of various versions of similar GCMs, it is clear that in some cases the vertical resolution of the atmosphere and, somewhat unexpectedly, of the adopted ocean model seem to be critical in determining the agreement with the reanalyses. The GCMs ensemble is biased with respect to the reanalyses but is comparable to the best 5 GCMs. This study suggests serious caveats with respect to the ability of most of the presently available GCMs in representing the statistics of the global scale atmospheric dynamics of the present climate and, a fortiori, in the perspective of modelling climate change.Comment: 39 pages, 8 figures, 2 table