Antibiotic dosing in the 'at risk' critically ill patient: Linking pathophysiology with pharmacokinetics/pharmacodynamics in sepsis and trauma patients

Background: Critical illness, mediated by trauma or sepsis, can lead to physiological changes that alter the pharmacokinetics of antibiotics and may result in sub-therapeutic concentrations at the sites of infection. The first aim of this project is to identify the clinical characteristics of critically ill patients with significant trauma that have been recently admitted to ICU that may predict the dosing requirements for the antibiotic, cefazolin. The second aim of this is to identify the clinical characteristics of critically ill patients with sepsis that may predict the dosing requirements for the combination antibiotic, piperacillin-tazobactam

Measuring quality of general reasoning

Machine learning models that automatically assess reasoning quality are trained on human-annotated written products. These “gold-standard” corpora are typically created by prompting annotators to choose, using a forced choice design, which of two products presented side by side is the most convincing, contains the strongest evidence or would be adopted by more people. Despite the increase in popularity of using a forced choice design for assessing quality of reasoning (QoR), no study to date has established the validity and reliability of such a method. In two studies, we simultaneously presented two products of reasoning to participants and asked them to identify which product was ‘better justified’ through a forced choice design. We investigated the criterion validity and inter-rater reliability of the forced choice protocol by assessing the relationship between QoR, measured using the forced choice protocol, and accuracy in objectively answerable problems using naive raters sampled from MTurk (Study 1) and experts (Study 2), respectively. In both studies products that were closer to the correct answer and products generated by larger teams were consistently preferred. Experts were substantially better at picking the reasoning products that corresponded to accurate answers. Perhaps the most surprising finding was just how rapidly raters made judgements regarding reasoning: On average, both novices and experts made reliable decisions in under 15 seconds. We conclude that forced choice is a valid and reliable method of assessing QoR

Cr(VI) Effect on Tc-99 Removal from Hanford Low-Activity Waste Simulant by Ferrous Hydroxide.

Here, Cr(VI) effects on Tc-immobilization by Fe(OH)2(s) are investigated while assessing Fe(OH)2(s) as a potential treatment method for Hanford low-activity waste destined for vitrification. Batch studies using simulated low-activity waste indicate that Tc(VII) and Cr(VI) removal is contingent on reduction to Tc(IV) and Cr(III). Furthermore, complete removal of both Cr and Tc depends on the amount of Fe(OH)2(s) present, where complete Cr and Tc removal requires more Fe(OH)2(s) (∼200 g/L of simulant), than removing Cr alone (∼50 g/L of simulant). XRD analysis suggests that Fe(OH)2(s) reaction and transformation in the simulant produces mostly goethite (α-FeOOH), where Fe(OH)2(s) transformation to goethite rather than magnetite is likely due to the simulant chemistry, which includes high levels of nitrite and other constituents. Once reduced, a fraction of Cr(III) and Tc(IV) substitute for octahedral Fe(III) within the goethite crystal lattice as supported by XPS, XANES, and/or EXAFS results. The remaining Cr(III) forms oxide and/or hydroxide phases, whereas Tc(IV) not fully incorporated into goethite persists as either adsorbed or partially incorporated Tc(IV)-oxide species. As such, to fully incorporate Tc(IV) into the goethite crystal structure, additional Fe(OH)2(s) (>200 g/L of simulant) may be required

The technologies of isolation: apocalypse and self in Kurosawa Kiyoshi's Kairo

In this investigation of the Japanese film Kairo, I contemplate how the horrors present in the film relate to the issue of self, by examining a number of interlocking motifs. These include thematic foci on disease and technology which are more intimately and inwardly focused that the film's conclusion first appears to suggest. The true horror here, I argue, is ontological: centred on the self and its divorcing from the exterior world, especially founded in an increased use of and reliance on communicative technologies. I contend that these concerns are manifested in Kairo by presenting the spread of technology as disease-like, infecting the city and the individuals who are isolated and imprisoned by their urban environment. Finally, I investigate the meanings of the apocalypse, expounding how it may be read as hopeful for the future rather than indicative of failure or doom

Validating a forced‑choice method for eliciting quality‑of‑reasoning judgments

In this paper we investigate the criterion validity of forced-choice comparisons of the quality of written arguments with normative solutions. Across two studies, novices and experts assessing quality of reasoning through a forced-choice design were both able to choose arguments supporting more accurate solutions—62.2% (SE = 1%) of the time for novices and 74.4% (SE = 1%) for experts—and arguments produced by larger teams—up to 82% of the time for novices and 85% for experts—with high inter-rater reliability, namely 70.58% (95% CI = 1.18) agreement for novices and 80.98% (95% CI = 2.26) for experts. We also explored two methods for increasing efficiency. We found that the number of comparative judgments needed could be substantially reduced with little accuracy loss by leveraging transitivity and producing quality-of-reasoning assessments using an AVL tree method. Moreover, a regression model trained to predict scores based on automatically derived linguistic features of participants’ judgments achieved a high correlation with the objective accuracy scores of the arguments in our dataset. Despite the inherent subjectivity involved in evaluating differing quality of reasoning, the forced-choice paradigm allows even novice raters to perform beyond chance and can provide a valid, reliable, and efficient method for producing quality-of-reasoning assessments at scale

TOM40 Mediates Mitochondrial Dysfunction Induced by α-Synuclein Accumulation in Parkinson's Disease.

Alpha-synuclein (α-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson's disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a component of the mitochondrial import machinery -TOM40- might contribute to the mitochondrial dysfunction and damage in PD. For this purpose, we studied levels of TOM40, mtDNA deletions, oxidative damage, energy production, and complexes of the respiratory chain in brain homogenates as well as in single neurons, using laser-capture-microdissection in transgenic mice overexpressing human wildtype α-Syn. Additionally, we used lentivirus-mediated stereotactic delivery of a component of this import machinery into mouse brain as a novel therapeutic strategy. We report here that TOM40 is significantly reduced in the brain of PD patients and in α-Syn transgenic mice. TOM40 deficits were associated with increased mtDNA deletions and oxidative DNA damage, and with decreased energy production and altered levels of complex I proteins in α-Syn transgenic mice. Lentiviral-mediated overexpression of Tom40 in α-Syn-transgenic mice brains ameliorated energy deficits as well as oxidative burden. Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in α-Synucleinopathies

Interleukin 6, lipopolysaccharide-binding protein and interleukin 10 in the prediction of risk and etiologic patterns in patients with community-acquired pneumonia: results from the German competence network CAPNETZ

<p>Abstract</p> <p>Background</p> <p>The aim of our study was to investigate the predictive value of the biomarkers interleukin 6 (IL-6), interleukin 10 (IL-10) and lipopolysaccharide-binding protein (LBP) compared with clinical CRB and CRB-65 severity scores in patients with community-acquired pneumonia (CAP).</p> <p>Methods</p> <p>Samples and data were obtained from patients enrolled into the German CAPNETZ study group. Samples (blood, sputum and urine) were collected within 24 h of first presentation and inclusion in the CAPNETZ study, and CRB and CRB-65 scores were determined for all patients at the time of enrollment. The combined end point representative of a severe course of CAP was defined as mechanical ventilation, intensive care unit treatment and/or death within 30 days. Overall, a total of 1,000 patients were enrolled in the study. A severe course of CAP was observed in 105 (10.5%) patients.</p> <p>Results</p> <p>The highest IL-6, IL-10 and LBP concentrations were found in patients with CRB-65 scores of 3-4 or CRB scores of 2-3. IL-6 and LBP levels on enrollment in the study were significantly higher for patients with a severe course of CAP than for those who did not have severe CAP. In receiver operating characteristic analyses, the area under the curve values for of IL-6 (0.689), IL-10 (0.665) and LPB (0.624) in a severe course of CAP were lower than that of CRB-65 (0.764) and similar to that of CRB (0.69). The accuracy of both CRB and CRB-65 was increased significantly by including IL-6 measurements. In addition, higher cytokine concentrations were found in patients with typical bacterial infections compared with patients with atypical or viral infections and those with infection of unknown etiology. LBP showed the highest discriminatory power with respect to the etiology of infection.</p> <p>Conclusions</p> <p>IL-6, IL-10 and LBP concentrations were increased in patients with a CRB-65 score of 3-4 and a severe course of CAP. The concentrations of IL-6 and IL-10 reflected the severity of disease in patients with CAP. The predictive power of IL-6, IL-10 and LBP for a severe course of pneumonia was lower than that of CRB-65. Typical bacterial pathogens induced the highest LBP, IL-6 and IL-10 concentrations.</p

Pregnancy Recruitment for Population Research: the National Children's Study Vanguard Experience in W ayne C ounty, M ichigan

Background To obtain a probability sample of pregnancies, the N ational C hildren's S tudy conducted door‐to‐door recruitment in randomly selected neighbourhoods in randomly selected counties in 2009–10. In 2011, an experiment was conducted in 10 US counties, in which the two‐stage geographic sample was maintained, but participants were recruited in prenatal care provider offices. We describe our experience recruiting pregnant women this way in W ayne C ounty, M ichigan, a county where geographically eligible women attended 147 prenatal care settings, and comprised just 2% of total county pregnancies. Methods After screening for address eligibility in prenatal care offices, we used a three‐part recruitment process: (1) providers obtained permission for us to contact eligible patients, (2) clinical research staff described the study to women in clinical settings, and (3) survey research staff visited the home to consent and interview eligible women. Results We screened 34 065 addresses in 67 provider settings to find 215 eligible women. Providers obtained permission for research contact from 81.4% of eligible women, of whom 92.5% agreed to a home visit. All home‐visited women consented, giving a net enrolment of 75%. From birth certificates, we estimate that 30% of eligible county pregnancies were enrolled, reaching 40–50% in the final recruitment months. Conclusions We recruited a high fraction of pregnancies identified in a broad cross‐section of provider offices. Nonetheless, because of time and resource constraints, we could enrol only a fraction of geographically eligible pregnancies. Our experience suggests that the probability sampling of pregnancies for research could be more efficiently achieved through sampling of providers rather than households.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97525/1/ppe12047.pd