Cationic/Anionic Poly(p-Phenylene Oxide) Membranes: Preparation and Electrodialysis Performance for Nickel Recovery from Industrial Effluents.

Electrodialysis (ED) has already been applied to recover nickel in galvanizing processes, allowing nickel recovery and the production of a treated effluent with demineralized water quality. However, the growth in ED use is still limited by the production and commercialization of ion-selective membranes, currently limited to a few large companies. Therefore, this paper presents the development of homogeneous cationic and anionic membranes made from poly(2,6-dimethyl-1,4-phenylene oxide) (PPO) for ED use.

Rare bleeding disorders: Real-world data from a Spanish tertiary hospital.

Introduction: Due to their low prevalence, rare bleeding disorders (RBDs) remain poorly characterized.

Aim: To gain insight of RBDs through our clinical practice.

Methods: Retrospective study of the medical records of RBD patients followed up at the Central University Hospital of Asturias between January 2019 and December 2022.

Applicability of the Thrombin Generation Test to Evaluate the Hemostatic Status of Hemophilia A Patients in Daily Clinical Practice.

Hemophilia A (HA) is a rare bleeding disorder caused by factor VIII (FVIII) deficiency due to various genetic mutations in the gene. The disease severity inversely correlates with the plasma levels of functional FVIII. The treatment of HA patients is based on FVIII replacement therapy, either following a prophylactic or on-demand regime, depending on the severity of the disease at diagnosis and the patient's clinical manifestations.

"Classifying D/s Profiles Without Prior Assumptions: An Application of Cluster Analysis to Social Data".

Dominant/submissive role-play (D/s) is associated with specialized roles including Mistress, Master, Slave, Switch, Sadist, and Masochist. The current study uses cluster analysis to provide empirical evidence that no binary opposition or single spectrum constitutes a workable typology of individuals based on their affinities for these roles. The optimality of a particular choice of clustering scheme, including the number of clusters, is established using a replication technique which is presented in detail.

Interprofessional primary care practice including social workers: exploring the experiences of patients in vulnerable situations.

The link between social inequality and health has been widely recognized, as there are systematic differences in health between people from lower and higher social classes. Furthermore, the complexity and multidimensionality of health and social problems has resulted in primary health care services that are increasingly integrating the approach of interprofessional collaboration between medical professionals and social workers. Despite this current focus, there is a lack of empirical insights into patients' experience of the quality of care resulting from these collaborations.

The DNA of Social Work as a Partner in Primary Health Care.

There is a strong focus on primary health care (PHC), as rooted in a commitment to social justice and equity, to reduce social inequalities in health. Within PHC, interprofessional collaboration is emphasized to achieve these objectives. Social workers are a renewed partner within these collaborations, as principles of social justice and human rights are the core of this profession.

Discovery of Milvexian, a High-Affinity, Orally Bioavailable Inhibitor of Factor XIa in Clinical Studies for Antithrombotic Therapy.

Factor XIa (FXIa) is an enzyme in the coagulation cascade thought to amplify thrombin generation but has a limited role in hemostasis. From preclinical models and human genetics, an inhibitor of FXIa has the potential to be an antithrombotic agent with superior efficacy and safety. Reversible and irreversible inhibitors of FXIa have demonstrated excellent antithrombotic efficacy without increased bleeding time in animal models (Weitz, J.

Discovery of a High Affinity, Orally Bioavailable Macrocyclic FXIa Inhibitor with Antithrombotic Activity in Preclinical Species.

Oral factor XIa (FXIa) inhibitors may provide a promising new antithrombotic therapy with an improved benefit to bleeding risk profile over existing antithrombotic agents. Herein, we report application of a previously disclosed cyclic carbamate P1 linker which provided improved oral bioavailability in the imidazole-based 13-membered macrocycle to the 12-membered macrocycle. This resulted in identification of compound with desired FXIa inhibitory potency and good oral bioavailability but high in vivo clearance.

Orally bioavailable amine-linked macrocyclic inhibitors of factor XIa.

The discovery of orally bioavailable FXIa inhibitors has been a challenge. Herein, we describe our efforts to address this challenge by optimization of our imidazole-based macrocyclic series. Our optimization strategy focused on modifications to the P2 prime, macrocyclic amide linker, and the imidazole scaffold.

Potent, Orally Bioavailable, and Efficacious Macrocyclic Inhibitors of Factor XIa. Discovery of Pyridine-Based Macrocycles Possessing Phenylazole Carboxamide P1 Groups.

Factor XIa (FXIa) inhibitors are promising novel anticoagulants, which show excellent efficacy in preclinical thrombosis models with minimal effects on hemostasis. The discovery of potent and selective FXIa inhibitors which are also orally bioavailable has been a challenge. Here, we describe optimization of the imidazole-based macrocyclic series and our initial progress toward meeting this challenge.

Structure based design of macrocyclic factor XIa inhibitors: Discovery of cyclic P1 linker moieties with improved oral bioavailability.

This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 9. This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 10, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 9.

Macrocyclic factor XIa inhibitors.

A series of macrocyclic factor XIa (FXIa) inhibitors was designed based on an analysis of the crystal structures of the acyclic phenylimidazole compounds. Further optimization using structure-based design led to inhibitors with pM affinity for FXIa, excellent selectivity against a panel of relevant serine proteases, and good potency in the activated partial thromboplastin time (aPTT) clotting assay.

Macrocyclic inhibitors of Factor XIa: Discovery of alkyl-substituted macrocyclic amide linkers with improved potency.

Optimization of macrocyclic inhibitors of FXIa is described which focused on modifications to both the macrocyclic linker and the P1 group. Increases in potency were discovered through interactions with a key hydrophobic region near the S1 prime pocket by substitution of the macrocyclic linker with small alkyl groups. Both the position of substitution and the absolute stereochemistry of the alkyl groups on the macrocyclic linker which led to improved potency varied depending on the ring size of the macrocycle.

Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker.

A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double-digit nanomolar FXIa inhibitors, were further optimized with assistance from utilization of structure-based drug design and ligand bound X-ray crystal structures. This effort resulted in the discovery of a macrocyclic amide linker which was found to form a key hydrogen bond with the carbonyl of Leu41 in the FXIa active site, resulting in potent FXIa inhibitors.

Orally bioavailable pyridine and pyrimidine-based Factor XIa inhibitors: Discovery of the methyl N-phenyl carbamate P2 prime group.

Pyridine-based Factor XIa (FXIa) inhibitor (S)-2 was optimized by modifying the P2 prime, P1, and scaffold regions. This work resulted in the discovery of the methyl N-phenyl carbamate P2 prime group which maintained FXIa activity, reduced the number of H-bond donors, and improved the physicochemical properties compared to the amino indazole P2 prime moiety. Compound (S)-17 was identified as a potent and selective FXIa inhibitor that was orally bioavailable.

Novel phenylalanine derived diamides as Factor XIa inhibitors.

The synthesis, structural activity relationships (SAR), and selectivity profile of a potent series of phenylalanine diamide FXIa inhibitors will be discussed. Exploration of P1 prime and P2 prime groups led to the discovery of compounds with high FXIa affinity, good potency in our clotting assay (aPPT), and high selectivity against a panel of relevant serine proteases as exemplified by compound 21. Compound 21 demonstrated good in vivo efficacy (EC50=2.

Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties.

Compound 2 was previously identified as a potent inhibitor of factor XIa lacking oral bioavailability. A structure-based approach was used to design analogs of 2 with novel P1 moieties with good selectivity profiles and oral bioavailability. Further optimization of the P1 group led to the identification of a 4-chlorophenyltetrazole P1 analog, which when combined with further modifications to the linker and P2' group provided compound 32 with FXIa Ki=6.

Pyridine and pyridinone-based factor XIa inhibitors.

The structure-activity relationships (SAR) of six-membered ring replacements for the imidazole ring scaffold is described. This work led to the discovery of the potent and selective pyridine (S)-23 and pyridinone (±)-24 factor XIa inhibitors. SAR and X-ray crystal structure data highlight the key differences between imidazole and six-membered ring analogs.

Phenylimidazoles as potent and selective inhibitors of coagulation factor XIa with in vivo antithrombotic activity.

Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg(-1) h(-1)).

tPA Alu (I/D) polymorphism associates with bacterial osteomyelitis.

Background: Coagulation and fibrinolysis are important in infections and systemic inflammatory response syndrome. Polymorphisms in plasminogen activator inhibitor-1 (PAI-1, SERPINE1) and tissue plasminogen activator (tPA, PLAT), such as PAI-1 (-675 4G/5G deletion/insertion) and tPA (Alu insertion/deletion [I/D]), are associated with strokes, myocardial infarctions, bacterial infections and septic shock severity, and trauma. Osteomyelitis is a mostly posttraumatic, Staphylococcal bone infection.

Impact of computerized physician order entry on medication errors.

Background: Information is scarce on the impact of the clinical electronic record on the frequency and severity of medication errors in acute geriatric patients.

Material And Methods: An analytical and descriptive pre-post study was conducted on the implementation of computerized provider order entry systems (CPOE), over a 6 year period. A voluntary reporting system was used to detect the medication errors using the IR2 report form of the UK National Health Service, the Global Trigger Tool and the walk rounds with the Pharmacy Service.

[Antimicrobial drugs errors: the silent epidemic in patient safety].

Introduction: Prescribed drugs and the mistakes in the administration to patient is the first cause of adverse events in the hospitals. The aim of this study has been to evaluate antimicrobial drug mistakes in one of our hospital wards in a two year period 2005 and 2006.

Methods: All the errors were reported through the National Health Service IR2 form (England) on a voluntary basis and classified by means of process, type of errors, their causes and contributory factors, as well as the severity.

Structure-activity relationships of anthranilamide-based factor Xa inhibitors containing piperidinone and pyridinone P4 moieties.

Introduction of the phenyl piperidinone and phenyl pyridinone P4 moieties in the anthranilamide scaffold led to potent, selective, and orally bioavailable inhibitors of factor Xa. Anthranilamide 28 displayed comparable efficacy to apixaban in the rabbit arteriovenous-shunt (AV) thrombosis model.

Synthesis and characterization of 3-arylquinazolinone and 3-arylquinazolinethione derivatives as selective estrogen receptor beta modulators.

On the basis of the stucture of genistein, a new series of 3-arylquinazolines was prepared and tested for their estrogen receptor (ER) alpha and beta affinities. 5,7-Dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinone (1aa) acts as an agonist on both ER subtypes. It has 62-fold higher binding affinity [IC(50)(ERbeta) = 179 nM] and 38-fold higher functional potency in a transcription assay [EC(50)(ERbeta) = 76 nM] with ERbeta than with ERalpha, thus improving upon the selectivity of genistein.