Technology requirements for advanced earth-orbital transportation systems, dual-mode propulsion

The application of dual-mode propulsion concepts to fully reusable single-stage-to-orbit (SSTO) vehicles is discussed. Dual-mode propulsion uses main rocket engines that consume hydrocarbon fuels as well as liquid hydrogen fuel. Liquid oxygen is used as the oxidizer. These engine concepts were integrated into transportation vehicle designs capable of vertical takeoff, delivering a payload to earth orbit, and return to earth with a horizontal landing. Benefits of these vehicles were assessed and compared with vehicles using single-mode propulsion (liquid hydrogen and oxygen engines). Technology requirements for such advanced transportation systems were identified. Figures of merit, including life-cycle cost savings and research costs, were derived for dual-mode technology programs, and were used for assessments of potential benefits of proposed technology activities. Dual-mode propulsion concepts display potential for significant cost and performance benefits when applied to SSTO vehicles

Technology requirements for advanced earth-orbital transportation systems: Summary report

Areas of advanced technology that are either critical or offer significant benefits to the development of future Earth-orbit transportation systems were identified. Technology assessment was based on the application of these technologies to fully reusable, single-state-to-orbit (SSTO) vehicle concepts with horizontal landing capability. Study guidelines included mission requirements similar to space shuttle, an operational capability beginning in 1995, and main propulsion to be advanced hydrogen-fueled rocket engines. The technical and economic feasibility of this class of SSTO concepts were evaluated as well as the comparative features of three operational take-off modes, which were vertical boost, horizontal sled launch, and horizontal take-off with subsequent inflight fueling. Projections of both normal and accelerated technology growth were made. Figures of merit were derived to provide relative rankings of technology areas. The influence of selected accelerated areas on vehicle design and program costs was analyzed by developing near-optimum point designs

How to improve drug dosing for patients with renal impairment in primary care - a cluster-randomized controlled trial

Background: Patients with chronic kidney disease (CKD) are at increased risk for inappropriate or potentially harmful prescribing. The aim of this study was to examine whether a multifaceted intervention including the use of a software programme for the estimation of creatinine clearance and recommendation of individual dosage requirements may improve correct dosage adjustment of relevant medications for patients with CKD in primary care. Methods: A cluster-randomized controlled trial was conducted between January and December 2007 in small primary care practices in Germany. Practices were randomly allocated to intervention or control groups. In each practice, we included patients with known CKD and elderly patients (>=70 years) suffering from hypertension. The practices in the intervention group received interactive training and were provided a software programme to assist with individual dose adjustment. The control group performed usual care. Data were collected at baseline and at 6 months. The outcome measures, analyzed across individual patients, included prescriptions exceeding recommended maximum daily doses, with the primary outcome being prescriptions exceeding recommended standard daily doses by 30% or more. Results: Data from 44 general practitioners and 404 patients are included. The intervention was effective in reducing prescriptions exceeding the maximum daily dose per patients, with a trend in reducing prescriptions exceeding the standard daily dose by more than 30%. Conclusions: A multifaceted intervention including the use of a software program effectively reduced inappropriately high doses of renally excreted medications in patients with CKD in the setting of small primary care practices

Indirect evidence for stimulation of nitric oxide release by tumour necrosis factor-α in human veins in vivo

Objectives: The detrimental haemodynamic changes observed in septicaemia are generalised vasodilation, arterial hypotension, and hyporesponsiveness to vasopressor compounds, all of which could be explained by the release of an endogenous vasodilator. Experimental and clinical evidence suggests that tumour necrosis factor-α (TNF) induces the expression of vascular nitric oxide (NO) synthase within hours and that NO released from smooth muscle cells could be involved in the pathogenesis of septic shock. The aim of this study was to investigate the role of NO in the vascular effects of TNF. Methods: Using the dorsal hand vein compliance technique, the effect of the NO synthase inhibitor L-NG-monomethyl-arginine (L-NMMA) on α1-adrenergic responsiveness (phenylephrine 1.25-8000 ng/min) was studied after prolonged local venous infusion of TNF (8.7 μg in 5 h) in 9 volunteers and in 6 volunteers without previous cytokine exposure. Results: Mean (±s.e.) maximum phenylephrine constriction (Emax) was 73 ± 6% and log dose-rates exerting 50% of Emax (log ED50) were 3.2 ± 0.09 (geometric mean: 1535 ng/min). Local co-administration of L-NMMA at a dose sufficiently high to block NO formation (3.4 μmol/min) increased venous sensitivity to phenylephrine threefold (log ED50 2.8 ± 0.1, P < 0.015; geometric mean: 574 ng/min) whereas Emax was similar (73 ± 5%). In the controls the phenylephrine dose-response relationship remained unaffected by simultaneous administration of L-NMMA. Conclusions: As no basal release of NO occurs in hand veins without previous exposure to TNF these results provide direct evidence for induction of NO formation in the human vasculature and consecutive resistance to α-adrenergic venoconstriction. NO might, therefore, be a key mediator of haemodynamic impairment in humans under conditions with known elevations of circulating TNF, such as a septic shoc

A European Turn in Early American History? A Discussion of Evan Haefeli's Accidental Pluralism: America and the Religious Politics of English Expansion, 1497-1662

From the nineteenth century onwards, Americans have naturalized their colonial origins into a consensual nationalist history, emphasizing America’s perceived role as a refuge for the persecuted, while smoothing out a myriad of complexities in the process. Evan Haefeli attempts to overturn the assumptions underpinning this narrative and is convinced that many important aspects of early America need to be understood within a broader European context. In Accidental Pluralism, he argues that the collapse of religious unity in England lies at the root of the emergence of pluralism in colonial America, in which he includes Canada and the Caribbean. Relationships among states, churches, and publics were contested from the earliest decades of colonization and created a pluralistic religious landscape that no one had anticipated. The four reviewers are fulsome in their praise, calling it an impressive, important, powerful, and sweeping book that few scholars could have written. The reviewers also raise questions, for instance by problematizing the incorporation of the colonial American dimension into early British history, criticizing the validity of the chosen end date, and questioning his definitions of diversity, pluralism, and religious toleration. In his response Evan Haefeli takes the opportunity to reflect on what drove him to write the book and to organize it in this way. He acknowledges that connecting early American history with its broader European context was more difficult than it should have been, as the dominant questions in the two historiographies are an ocean apart. While the argument of the book is aimed at early Americanists, Haefeli is grateful that the reviewers situate the story he tells within the broader early modern European history of toleration

Time Course of the Interaction Between Oral Short-Term Ritonavir Therapy with Three Factor Xa Inhibitors and the Activity of CYP2D6, CYP2C19, and CYP3A4 in Healthy Volunteers

Background We investigated the effect of a 5-day low-dose ritonavir therapy, as it is used in the treatment of COVID-19 with nirmatrelvir/ritonavir, on the pharmacokinetics of three factor Xa inhibitors (FXaI). Concurrently, the time course of the activities of the cytochromes P450 (CYP) 3A4, 2C19, and 2D6 was assessed. Methods In an open-label, fixed sequence clinical trial, the effect and duration of a 5-day oral ritonavir (100 mg twice daily) treatment on the pharmacokinetics of three oral microdosed FXaI (rivaroxaban 25 µg, apixaban 25 µg, and edoxaban 50 µg) and microdosed probe drugs (midazolam 25 µg, yohimbine 50 µg, and omeprazole 100 µg) was evaluated in eight healthy volunteers. The plasma concentrations of all drugs were quantified using validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) methods and pharmacokinetics were analysed using non-compartmental analyses. Results Ritonavir increased the exposure of apixaban, edoxaban, and rivaroxaban, but to a different extent the observed area under the plasma concentration–time curve (geometric mean ratio 1.29, 1.46, and 1.87, respectively). A strong CYP3A4 inhibition (geometric mean ratio > 10), a moderate CYP2C19 induction 2 days after ritonavir (0.64), and no alteration of CYP2D6 were observed. A CYP3A4 recovery half-life of 2.3 days was determined. Conclusion This trial with three microdosed FXaI suggests that at most the rivaroxaban dose should be reduced during short-term ritonavir, and only in patients receiving high maintenance doses. Thorough time series analyses demonstrated differential effects on three different drug-metabolising enzymes over time with immediate profound inhibition of CYP3A4 and only slow recovery after discontinuation. Clinical Trial Registration EudraCT number: 2021-006643-39

Associations of frailty with health care costs – results of the ESTHER cohort study

Background: The concept of frailty is rapidly gaining attention as an independent syndrome with high prevalence in older adults. Thereby, frailty is often related to certain adverse outcomes like mortality or disability. Another adverse outcome discussed is increased health care utilization. However, only few studies examined the impact of frailty on health care utilization and corresponding costs. The aim of this study was therefore to investigate comprehensively the relationship between frailty, health care utilization and costs. Methods: Cross sectional data from 2598 older participants (57–84 years) recruited in the Saarland, Germany, between 2008 and 2010 was used. Participants passed geriatric assessments that included Fried’s five frailty criteria: weakness, slowness, exhaustion, unintentional weight loss, and physical inactivity. Health care utilization was recorded in the sectors of inpatient treatment, outpatient treatment, pharmaceuticals, and nursing care. Results: Prevalence of frailty (≥3 symptoms) was 8.0 %. Mean total 3-month costs of frail participants were €3659 (4 or 5 symptoms) and €1616 (3 symptoms) as compared to €642 of nonfrail participants (no symptom). Controlling for comorbidity and general socio-demographic characteristics in multiple regression models, the difference in total costs between frail and non-frail participants still amounted to €1917; p < .05 (4 or 5 symptoms) and €680; p < .05 (3 symptoms). Among the 5 symptoms of frailty, weight loss and exhaustion were significantly associated with total costs after controlling for comorbidity. Conclusions: The study provides evidence that frailty is associated with increased health care costs. The analyses furthermore indicate that frailty is an important factor for health care costs independent from pure age and comorbidity. Costs were rather attributable to frailty (and comorbidity) than to age. This stresses that the overlapping concepts of multimorbidity and frailty are both necessary to explain health care use and corresponding costs among older adults

The Role of Adherence Thresholds for Development and Performance Aspects of a Prediction Model for Direct Oral Anticoagulation Adherence

Patients who do not sufficiently adhere to their dosing regimens will, ultimately, do not get the full benefit of their medication. For example, if direct oral anticoagulants (DOAC) are not taken continuously, an intervention to improve adherence or maintain persistence will show direct effects on clinical outcomes. Usually, adherent patients are defined by taking ≥80% of their medication. The resulting binary adherence status from this threshold can as well be used for predictive classification. Thus, the threshold can determine the prediction model’s performance to identify patients at risk for poor adherence by this binary adherence status. In this perspective, we propose a plan for model development and performance considering the threshold’s role. Concerning development demands, we extracted predictors from a systematic literature search on DOAC adherence to be used as a core set of candidate predictors. Independently, we investigated how well a future model would technically have to perform by modeling drug intake and thromboembolic events based on a rivaroxaban pharmacokinetic-pharmacodynamic model. Using this simulation framework for different thresholds, we projected the impact of an imperfectly predicted adherence status on the event risk, and how imperfect sensitivity and specificity affect the cost balance if a supporting intervention was offered to patients classified as non-adherent. Our simulation results suggest applying a rather high threshold (90%) for discrimination between patients at low or high risk for non-adherence by a prediction model in order to assure cost-efficient implementation