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Activated coagulation factor XI (FXIa) is a highly attractive antithrombotic target as it contributes to the development and progression of thrombosis but is thought to play only a minor role in hemostasis so that its inhibition may allow for decoupling of antithrombotic efficacy and bleeding time prolongation. Herein, we report our major efforts to identify an orally bioavailable, reversible FXIa inhibitor. Using a protein structure-based de novo design approach, we identified a novel micromolar hit with attractive physicochemical properties. During lead modification, a critical problem was balancing potency and absorption by focusing on the most important interactions of the lead series with FXIa while simultaneously seeking to improve metabolic stability and the cytochrome P450 interaction profile. In clinical trials, the resulting compound from our extensive research program, asundexian (BAY 2433334), proved to possess the desired DMPK properties for once-daily oral dosing, and even more importantly, the initial pharmacological hypothesis was confirmed.

Background: Activated coagulation factor XI (FXIa) contributes to the development and propagation of thrombosis but plays only a minor role in hemostasis; therefore, it is an attractive antithrombotic target., Objectives: To evaluate the pharmacology of asundexian (BAY 2433334), a small molecule inhibitor targeting FXIa, in vitro and in various rabbit models., Methods: The effects of asundexian on FXIa activity, selectivity versus other proteases, plasma thrombin generation, and clotting assays were evaluated. Antithrombotic effects were determined in FeCl 2 - and arterio-venous (AV) shunt models. Asundexian was administered intravenously or orally, before or during thrombus formation, and with or without antiplatelet drugs (aspirin and ticagrelor). Potential effects of asundexian on bleeding were evaluated in ear-, gum-, and liver injury models., Results: Asundexian inhibited human FXIa with high potency and selectivity. It reduced FXIa activity, thrombin generation triggered by contact activation or low concentrations of tissue factor, and prolonged activated partial thromboplastin time in human, rabbit, and various other species, but not in rodents. In the FeCl 2 -injury models, asundexian reduced thrombus weight versus control, and in the arterial model when added to aspirin and ticagrelor. In the AV shunt model, asundexian reduced thrombus weight when administered before or during thrombus formation. Asundexian alone or in combination with antiplatelet drugs did not increase bleeding times or blood loss in any of the models studied., Conclusions: Asundexian is a potent oral FXIa inhibitor with antithrombotic efficacy in arterial and venous thrombosis models in prevention and intervention settings, without increasing bleeding., (© 2022 Bayer AG. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Despite extensive research on small molecule thrombin inhibitors for oral application in the past decades, only a single double prodrug with very modest oral bioavailability has reached human therapy as a marketed drug. We have undertaken major efforts to identify neutral, non-prodrug inhibitors. Using a holistic analysis of all available internal data, we were able to build computational models and apply these for the selection of a lead series with the highest possibility of achieving oral bioavailability. In our design, we relied on protein structure knowledge to address potency and identified a small window of favorable physicochemical properties to balance absorption and metabolic stability. Protein structure information on the pregnane X receptor helped in overcoming a persistent cytochrome P450 3A4 induction problem. The selected compound series was optimized to a highly potent, neutral, non-prodrug thrombin inhibitor by designing, synthesizing, and testing derivatives. The resulting optimized compound, BAY1217224, has reached first clinical trials, which have confirmed the desired pharmacokinetic properties.

To prevent thromboses after surgery, patients have until now had to inject themselves daily with heparin. For stroke prophylaxis in atrial fibrillation, patients take vitamin K antagonists of the coumarin type, which have a narrow therapeutic window and whose dosage must be regularly monitored. In order to improve the standard of therapy in thromboembolic diseases such as deep-vein thrombosis, pulmonary embolism, and stroke in atrial fibrillation, intensive research has been carried out over the last decade in the search for new, orally active thrombin and factor Xa inhibitors. A number of these compounds are already on the market or are in advanced clinical development; they could revolutionize the anticoagulant market., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aims: We investigated risk factors and neonatal outcomes of preeclampsia., Methods: We analyzed data of the German Perinatal Quality Registry 2006 that contains the complete national birth cohort of 668,085 newborn infants and 647,392 mothers from 917 German obstetric clinics., Results: The prevalence of preeclampsia in 2006 was at 2.31%. Higher maternal age, gestational diabetes, no previous as well as multiple births, pre-pregnancy obesity and above-average weight gain during pregnancy were significantly associated with preeclampsia. A positive relationship between social burden (e.g., low social status, psychosocial stress) and the risk of preeclampsia appeared. Smoking appeared to be negatively correlated. Neonatal complications associated with preeclampsia in the study were small babies, acute respiratory distress syndrome, postpartum neonatal hypoglycemia and low Apgar scores. We did not observe an increased rate of stillbirths with preeclampsia pregnancies., Conclusions: Further studies and interventions regarding prenatal care should not focus only on how better diagnostic and treatment procedures can be implemented but also on how these diagnostic and treatment procedures can reach high-risk groups.

Objective: This study aimed to identify risk factors for gestational diabetes mellitus (GDM) and assess the effects of GDM on the risk of adverse pregnancy outcomes., Material and Methods: This was a cross-sectional study using data from the German Perinatal Quality Registry, which is a complete national registry containing information on all hospital births across Germany. The Registry for 2006 contains data on a complete birth cohort of 668,085 newborn infants and 647,392 mothers from all 896 German hospitals. All data were taken from maternity log records and analyzed by multivariate logistic regression. Each recorded case of GDM was identified by a gynecologist or in hospital., Results: The prevalence of GDM was 2.3% (14,990 of 647,385). High-risk groups were migrants, women of lower socioeconomic status (adjusted odds ratio 1.16, 95% confidence interval 1.05-1.28) and obese women (adjusted odds ratio 4.96, 95% confidence interval 4.70-5.24). A higher risk of fetal malformations was found for those diagnosed with GDM (adjusted odds ratio 1.32, 95% confidence interval 1.15-1.53)., Conclusion: The higher risk of fetal malformations with GDM suggests that many of these women may have high glucose levels even during the first trimester. Policies and interventions regarding prenatal care should therefore focus not only on how better diagnostic and treatment procedures can be implemented, but also on how they can reach older and migrant women as well as women of lower socioeconomic status., (© 2010 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2010 Nordic Federation of Societies of Obstetrics and Gynecology.)

The activated serine protease factor Xa is a promising target for new anticoagulants. After studies on naturally occurring factor Xa inhibitors indicated that such agents could be effective and safe, research focused on small-molecule direct inhibitors of factor Xa that might address the major clinical need for improved oral anticoagulants. In 2008, rivaroxaban (Xarelto; Bayer HealthCare) became the first such compound to be approved for clinical use. This article presents the history of rivaroxaban's development, from the structure-activity relationship studies that led to its discovery to the preclinical and clinical studies, and also provides a brief overview of other oral anticoagulants in advanced clinical development.

Objectives: This study investigated the real motives of German non-smokers., Methods: In the German SToP ("Sources of Tobacco for Pupils") Study 707 non-smoking pupils were asked to write down their motives for being non-smokers. A total of 1324 partially very elaborate free text statements (mean/range: 1.9/1-7 distinguishable motives) were evaluated in a qualitative content analysis., Results: The most important and frequently mentioned motives for not smoking were health-related arguments (78.1%). Except for cancer significant main health risks of tobacco consumption like cardio- and cerebrovascular diseases or COPD were hardly perceived. Further important reasons were an aesthetic aversion (38.6%), missing perception of a benefit (25.2%), and economic motives (20.8%). Girls and pupils from academic high schools named aesthetic motives significantly more often than boys and pupils from secondary schools respectively. A historical comparison shows that the motive "lacking benefit" reached a higher rank in our study than in the 1990s., Conclusions: When non-smokers are asked directly, extrinsic reasons (restrictions, smoking bans) do not seem to be relevant for them. Reasons concerning health, good physical shape, and beauty should be a central argument in the medical practise with young smokers., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Rivaroxaban is a direct inhibitor of factor Xa, a coagulation factor at a critical juncture in the blood coagulation pathway leading to thrombin generation and clot formation. It is selective for human factor Xa, for which it has >10 000-fold greater selectivity than for other biologically relevant serine proteases (half-maximal inhibitory concentration [IC(50)], >20 micromol/L). Rivaroxaban inhibits factor Xa in a concentration-dependent manner (inhibitory constant [K(i)], 0.4 nmol/L) and binds rapidly (kinetic association rate constant [k(on)], 1.7x10(7) mol/L(-1) s(-1)) and reversibly (kinetic dissociation rate constant [k(off)], 5x10(-3) s(-1)). By inhibiting prothrombinase complex-bound (IC(50), 2.1 nmol/L) and clot-associated factor Xa (IC(50), 75 nmol/L), rivaroxaban reduces the thrombin burst during the propagation phase. In animal models of venous and arterial thrombosis, rivaroxaban showed dose-dependent antithrombotic activity. In healthy individuals, rivaroxaban was found to have predictable pharmacokinetics and pharmacodynamics across a 5- to 80-mg total daily dose range, inhibiting factor Xa activity and prolonging plasma clotting time. In phase III clinical trials, rivaroxaban regimens reduced rates of venous thromboembolism in patients after total hip or knee arthroplasty compared with enoxaparin regimens, without significant differences in rates of major bleeding, showing that rivaroxaban has a favorable benefit-to-risk profile.

Background: The aim of this study was to evaluate the efficacy and toxic side effects of combined gemcitabine plus weekly high-dose 5-Fluorouracil (5-FU) as 24h-infusion in patients with metastatic pancreatic cancer (UICC IV) as validation group of an earlier phase II study. Primary endpoints were to assess the response and tumour control rate., Material/methods: This study comprised 60 prospectively registered patients with metastatic pancreatic cancer (UICC IV). A locally advanced disease was defined as exclusion criteria. The treatment schedule was weekly gemcitabine (1.000 mg/m(2)) as a 0.5h-infusion combined with 5-FU (2.000 mg/m(2)) as a 24h-infusion on day 1, 8 and 15 every 28 days., Results: Response rate (CR+PR) was achieved in 7% of the patients, tumour control rate (CR+PR+SD) was achieved in 59%. Median time-to-progression was 4 months, median overall survival was 7.3 months (95% CI 5.4-9.1). The median survival of patients with normal CEA value was 10.6 months (95% CI 7.8-13.4); with a normal CA 19-9 median survival was 10.1 months (95% CI 4.6-15.7) and with ECOG performance status 0 median survival was 10.1 months (95% CI 8.6-15.3). As higher grade toxicity (grade 3/4) leukopenia (15%), anaemia (10%) and thrombopenia (5%) were observed. Nausea and diarrhea (grade 3/4) occurred in 5% of the patients and vomiting in 2%., Conclusions: The administration of gemcitabine and 5-FU as a 24h-infusion is feasible and offers good tumour control rate accompanied by tolerable toxicity. The subgroup of patients with a good performance status (ECOG 0) and tumour markers within the normal range benefit from the gemcitabine combination therapy.

Several clinical candidates have now emerged as a result of an intense search for orally available, antithrombotic factor Xa inhibitors. This review highlights the discovery of XareltoTM (Rivaroxaban) starting from an initial tetrahydrophthalimide screening hit. The major breakthrough was the finding that a chlorothiophene moiety can undergo an interaction in the S1 binding site thus leading to high potency combined with favorable oral bioavailability. The binding mode of this P1 moiety is discussed, and further non-basic S1 binders of this new type are reviewed.

Purpose: This case report describes the effects of a new ankle foot orthosis with bi-channel adjustable ankle locks combined with physical therapy intervention on gait parameters in a subject with longstanding hemiplegia., Clinical Problem: A 69-year old male, 4.5 years post cerebrovascular accident with residual right hemiplegia, demonstrated impaired lower extremity muscle performance and motor control, with difficulty performing graded knee extension and achieving active knee flexion except in synergy, and slow gait (0.34 m/sec) with decreased left step time (0.57 sec) and length (26.3 cm) compared to the right (1.26 sec and 35.5 cm, respectively), decreased foot clearance during swing and knee hyperextension during stance., Intervention: Collaboration between the PT and orthotist with attention to the subject's knee control and history of lower extremity edema determined orthotic prescription. The subjects then received 24 outpatient physical therapy visits over 11 weeks., Results: The new orthosis and PT intervention resulted in improved foot clearance, usual and fast velocity, with increased cadence, and better step length differential and step time differential at usual speed. Following physical therapy, muscle performance of quadriceps and hamstring improved, with no knee hyperextension during stance. The subject demonstrated increased confidence in gait and a positive attitude toward his right lower extremity., Conclusions: An appropriate orthosis combined with PT intervention can decrease energy expenditure in walking and increase confidence and attitude in a subject with longstanding hemiplegia.

MEASURES USED TO PROTECT SUBJECTS in publicly distributed microdata files often have a significant negative impact on key analytic uses of the data. For example, it may be important to analyze subpopulations within a data file such as racial minorities, yet these subjects may present the greatest disclosure risk because their records tend to stand out or be unique. Files or records that are linkable create another type of disclosure risk-common elements between two files can be used to link files with sensitive data to externally available files that disclose identity. Examples of disclosure limitation methods used to address these types of issues include blanking out data, coarsening response categories, or withholding data altogether. However, the very detail that creates the greatest risk also provides insight into differences that are of greatest interest to analysts. Restricted-use agreements that provide unaltered versions of the data may not be available, or only selectively so. The public-use version of the data is very important because it is likely to be the only one to which most researchers, policy analysts, teaching faculty, and students will ever have access. Hence, it is the version from which much of the utility of the data is extracted and often it effectively becomes the historical record of the data collection. This underscores the importance that the disclosure review c ommittee s trikes a g ood b alance b etween protection and u tility. In this paper we d escrib e our disclosure review committee's (DRC) analysis and resulting data protection plans for two national studies and one administrative data system. Three distinct disclosure limitation methods were employed, taking key uses of the data into consideration, to protect respondents while still providing statistically accurate and highly useful public-use data. The techniques include data swapping, microaggregation, and suppression of detailed geographic data. We describe the characteristics of the data sets that led to the selection of these methods, provide measures of the statistical impact, and give details of their implementations so that others may also utilize them. We briefly discuss the composition of our DRC, highlighting what we believe to be the important disciplines and experience represented by the group.

In the eukaryotic cell, exchange of biomolecules between nucleus and cytoplasm is a highly regulated process which responds sensitively to changes of the environment. One well-known cellular response to environmental challenges is cell death by apoptosis. In fact, apoptosis has been shown to affect the nucleocytoplasmic transport machinery, in particular the nuclear pore, by modulating its size exclusion limit for passive diffusion. The underlying molecular factors are still unknown, mainly because of the lack of a suitable system to detect and quantitate the apoptotic effects on the nuclear pore. Here we present an assay that was designed to measure alterations of the permeability of the nuclear envelope under apoptotic conditions. The assay is based on the well-established technique of selective permeabilization of the plasma membrane with digitonin and allows assessment of permeability changes in nonfixed samples. It comprises a computer program, called Nuclear Permeability Assay, for the quantitation of the nuclear fluorescence signal, which may be generally employed for the evaluation of in vitro transport systems using semipermeabilized cells, such as assays for nuclear import and export.

Information on establishing the organizational structure of sports medicine clinics is useful to clinicians intending to start or expand a clinic. The purpose of this study was to identify an organizational model of existing sports medicine facilities in terms of: 1) administration and management, 2) staff qualifications and professional development, 3) location of facility, 4) range of services, 5) availability of services, 6) physician referral base, and 7) fee structure. A survey of 250 sports medicine clinics located in or near urban cities across the United States was conducted by mail. Results of this study indicate that the typical sports medicine facility is corporate-owned. A physical therapist and/or a physician establishes policy, and the physical therapist directs day-to-day operations. On average, the professional staff have four years of athletic team affiliation and seven years of clinical experience with athletes. The staff have attended less than an average of one continuing education course a year over the last five years. The typical facility is located within five miles of a major city, within 10 miles of its primary referral source and competition, and within 10 miles of its clients' homes. Most facilities employ combinations of full-time and part-time physicians, physical therapists, and athletic trainers. The typical sports medicine facility is open 12 hours each weekday. The physician referral base is composed primarily of orthopaedic and family practice physicians who refer an average of 14 new patients a week. J Orthop Sports Phys Ther 1992;15(2):80-86.

The primary purpose of this study was to determine which information available on applicants to the University of New Mexico physical therapy program would best predict performance on the licensing examination. The secondary purpose was to provide documentation of a procedure for selection that could be useful to other programs in other settings. American College Testing (ACT) scores, prerequisite and nonprerequisite grade point averages (GPAs), and interview and recommendation scores were used to predict licensing examination scores for the classes graduating from 1980 to 1984. Six of the regression analyses were significant, but three had similar correlations that were much higher than the rest. The variables in those three regression analyses were ACT composite score and both GPAs; ACT composite score, both GPAs, and interview score; and ACT composite score, prerequisite GPA, and interview score. The results of this study suggest that selection committees use standardized ability tests as admission criteria because the ACT scores accounted for the most variance in licensing examination scores. Other professional schools might also benefit by applying the procedures used in this study to their own data to develop prediction equations.