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1.
Nurse Educ ; 2024 Apr 17.
Article de Anglais | MEDLINE | ID: mdl-38640455

RÉSUMÉ

BACKGROUND: To prepare nursing students to deliver high-quality care, educators need strategies to foster person-centered care (PCC). PURPOSE: This pilot study evaluated an intervention with interactive case studies on undergraduate nursing students' PCC competency. METHODS: We conducted a pilot study with sophomore undergraduate nursing students (n = 39) from a Midwestern US university. We developed a 90-minute class seminar with interactive case studies highlighting how patient preferences, values, and circumstances could influence fall risk. We assessed PCC using the Patient-Centered Care Competency Scale. RESULTS: Although there was no statistically significant change in overall PCC competency before and after the intervention, we noted a small to medium effect size on PCC competency per Cohen's d standards (d = 0.35). Content analysis of students' open-ended responses reflected PCC and clustered into 5 themes. CONCLUSIONS: Findings suggest that educators may use interactive case studies to foster nursing student PCC competency.

3.
Conscious Cogn ; 115: 103581, 2023 10.
Article de Anglais | MEDLINE | ID: mdl-37847944

RÉSUMÉ

In an item-method directed forgetting task, memory instructions presumably operate by promoting further rehearsal of to-be-remembered (TBR) items and limiting encoding of to-be-forgotten (TBF) items. We asked whether diverting attentional resources away from TBF items and towards a new item that needed to be committed to memory would improve forgetting. To this end, study words in our experiments were presented singly followed by a remember instruction (single-TBR), by a forget instruction (single-TBF), or else were replaced by a new word to be remembered (replace-TBR) in place of the original study word which could be forgotten (replace-TBF). A typical directed forgetting effect was observed across single and replace trials. However, there was no compelling evidence that forgetting was better for replace-TBF compared to single-TBF words, suggesting that, by itself, the explicit redirection of attentional and other processing resources away from forget items may not be sufficient to improve item-method directed forgetting.


Sujet(s)
Électroencéphalographie , Potentiels évoqués , Humains , Signaux , Temps de réaction , Rappel mnésique
4.
J Pain Symptom Manage ; 66(4): e461-e468, 2023 10.
Article de Anglais | MEDLINE | ID: mdl-37343901

RÉSUMÉ

CONTEXT: Communication quality in the hospital impacts outcomes like satisfaction, depression, and anxiety for families, and assessment tools must be efficient and reliable. OBJECTIVES: We developed the Quick FICS-5 and -10, shorter versions of the 30-item Family Inpatient Communication Survey (FICS). METHODS: The Quick FICS were developed from the original FICS study of hospitalized patients 65+ and their surrogates. The development sample came from the original FICS-30 scale. The validation sample came from a randomized controlled trial of surrogates for adult ICU patients. Participants were family members of patients on medical ICU or inpatient medicine services at three hospitals in a Midwest metropolitan area. We evaluated validity and reliability using factor analysis, internal consistency, and associations with surrogate psychological and decision-making outcomes. RESULTS: In the development sample of 364 patient/surrogate dyads, most surrogates were adult children (66.8%), female (70.9%), and white (68.9%). We identified 5-item and 10-item surveys. Exploratory factor analysis supported an overall communication score for the FICS-5 and FICS-10, as well as information and emotional support subscales for the FICS-10. There was high internal reliability (Cronbach's alpha was 0.83 for the FICS-5 and 0.90 for the FICS-10; information and emotional support subscales were 0.89 and 0.75 respectively). There was good predictive validity when comparing FICS scores to outcomes six to eight weeks after discharge, including anxiety (P = -0.13; P = 0.0234), and satisfaction with the hospital stay (P = 0.48; P < 0.0001). Similarly, the validation sample (n = 188) revealed Cronbach's alpha ranging from 0.81 to 0.93 and significant correlations (P < 0.05) with concurrent distress, anxiety, depression, and decision regret. CONCLUSIONS: The Quick FICS offers efficient, valid, and reliable evaluation of communication quality in the hospital that can be useful for research and quality improvement.


Sujet(s)
Communication , Patients hospitalisés , Adulte , Femelle , Humains , Anxiété/psychologie , Psychométrie , Reproductibilité des résultats , Enquêtes et questionnaires , Mâle
5.
Nurs Educ Perspect ; 44(1): 63-65, 2023.
Article de Anglais | MEDLINE | ID: mdl-34966073

RÉSUMÉ

ABSTRACT: Teaching dermatologic conditions can be challenging in lecture-style format. A class activity was implemented in a prelicensure nursing course to enhance learning of dermatologic conditions while emphasizing the nursing process, evidence-based treatments, transmission-based precautions, and teamwork. Students worked in teams to identify moulage-based dermatologic conditions and follow the nursing process to develop a plan of care. Students presented their findings to faculty and peers. Positive student feedback on the activity included enhanced teamwork, application of the nursing process, visual emphasis on content, and understanding of holistic care. This activity is an innovative alternative to traditional lecture format.


Sujet(s)
Dermatologie , Élève infirmier , Enseignement , Humains , Modèles anatomiques , Démarche de soins infirmiers , Apprentissage par problèmes , Élève infirmier/psychologie , Dermatologie/enseignement et éducation
6.
J Pain Symptom Manage ; 65(4): 296-307, 2023 04.
Article de Anglais | MEDLINE | ID: mdl-36526251

RÉSUMÉ

CONTEXT: Critical illness of a family member is associated with high emotional and spiritual distress and difficult medical decisions. OBJECTIVES: To determine if a semistructured spiritual care intervention improves the well-being of family surrogate decision makers in intensive care (ICU) settings. METHODS: This study is a randomized, allocation-concealed, parallel group, usual care-controlled, single-blind trial of patient/surrogate dyads in five ICUs in one Midwest, academic medical center. Patients were 18 and older admitted to the ICU and unable to make medical decisions. The intervention involved proactive contact from the chaplain, scheduled, semi-structured visits, weekly follow-up, and bereavement calls. The control group received usual care. The primary endpoint was the surrogate's anxiety (Generalized Anxiety Disorders-7 scale), six to eight weeks after discharge. RESULTS: Of 192 patient/surrogate dyads enrolled, 128 completed outcome assessments. At follow-up, anxiety in the intervention group was lower than control (median score 1 (interquartile range 0,6) vs. 4 (1,9), P = 0.0057). The proportion of patients with a minimal clinically important difference (MCID) in anxiety of 2+ was 65.2% in the intervention group vs. 49.2% in control. The odds of an MCID remained higher in adjusted analysis (Odds Ratio 3.11, 95% confidence interval 1.18, 8.21; P = 0.0218) The adjusted odds of an MCID were higher for spiritual well-being (OR 3.79, CI 1.41,10.17; P = 0.0081). Satisfaction with spiritual care was also higher (adjusted mean 3.5 ± 0.4 vs. 2.9 ± 0.1); P < .0001). CONCLUSIONS: Proactive, semistructured spiritual care delivered by chaplains improves well-being for ICU surrogates. Results provide evidence for inclusion of chaplains in palliative and intensive care teams.


Sujet(s)
Prise de décision , Thérapies spirituelles , Humains , Méthode en simple aveugle , Soins de réanimation , Spiritualité , Unités de soins intensifs , Famille/psychologie
7.
J Psychiatr Ment Health Nurs ; 30(3): 558-567, 2023 Jun.
Article de Anglais | MEDLINE | ID: mdl-36579628

RÉSUMÉ

WHAT IS KNOWN ON THE SUBJECT?: It is known that people with a diagnosis of borderline personality disorder often experience crises in their mental wellbeing. There is little evidence about the approaches of mental health nurses in community-based crisis teams when working with people with a diagnosis of BPD. WHAT THE PAPER ADDS TO THE EXISTING KNOWLEDGE?: This paper highlights that limited resources, work-patterns and issues of stigma present challenges to delivering recovery-oriented care. The paper highlights that nurses typically try to navigate the challenges to continue to provide individualized care, though their self-assessment is that this is with mixed success. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: The findings suggest that support is needed to develop brief interventions specific to teams working with people with a diagnosis of BPD who are at a point of crisis. ABSTRACT: Introduction People with a diagnosis of borderline personality disorder (BPD) are often in contact with mental health services at a point of crisis, and in the UK, this includes Crisis Resolution Home Treatment teams (CRHTT). There is a drive for services to be recovery orientated; however, there is little evidence about the degree to which community services achieve this for people with a diagnosis of BPD when in crisis. Research Aim To understand the perceptions held by CRHTT clinicians about their provision of recovery-orientated acute care, for people with a diagnosis of BPD. Method From a purposive sample of a single CRHTT, seven registered mental health nurses were interviewed and Braun and Clarke's thematic analysis framework was used to interpret the data. Results Five themes emerged: person-centred care; the timing is wrong; inconsistent staffing; the risks are too great; and BPD as a label. Discussion The results demonstrate tensions between a drive to deliver person-centred care and a range of challenges that inhibit this, with the possibility of reframing a recovery approach as "recovery-ready". Implications for Practice A whole-system approach is required to enable a consistent recovery-oriented approach, but research is also needed for brief interventions specific to this context.


Sujet(s)
Trouble de la personnalité limite , Services de santé mentale , Soins infirmiers en psychiatrie , Humains , Trouble de la personnalité limite/diagnostic , Trouble de la personnalité limite/thérapie , Trouble de la personnalité limite/psychologie , Plan de recherche
8.
Front Sports Act Living ; 4: 792703, 2022.
Article de Anglais | MEDLINE | ID: mdl-35156016

RÉSUMÉ

Women with disability often experience barriers to employment and career progression, most notably in hyper-masculinised industry sectors such as sport. Applying an intersectionality lens and insights from critical disability theory, this research explores the lived experiences of eight women with varying types of disability through their stories of working and volunteering in sport organizations in Victoria (Australia). Analyses of the interviews highlighted the importance that these women attached to their identity as a woman with disability and the intrapersonal and organizational factors that impacted on initial sport workplace attraction and retention. The findings discuss the relationship management strategies adopted to manage these factors in workplace interactions. The interactive effect between disability and gender contributes to building a meaningful understanding of the intersectionality for women with disability in sport organizations.

10.
Mem Cognit ; 49(6): 1101-1118, 2021 08.
Article de Anglais | MEDLINE | ID: mdl-33650022

RÉSUMÉ

Intentional forgetting of unwanted items is effortful, yet directed forgetting seems to improve when a secondary task is performed. According to the cognitive load hypothesis of directed forgetting, allocating attentional resources to another task improves forgetting by restricting unwanted encoding of to-be-forgotten (TBF) items. Alternatively, it might be that anything that makes studying more difficult will encourage greater effort to perform the task well and therefore lead to improved intentional forgetting. To assess these proposals we imposed data-processing limitations on study words in an item-method directed forgetting paradigm. Across six experiments, the perceptual quality of study words was manipulated by varying: (1) the duration of study word presentation (Experiments 1-4); (2) the contrast of the displayed word against its visual background (Experiment 5); or (3) the amount of visual background noise on which the word was presented (Experiment 6). In Experiments 4-6, a lexical decision task corroborated the difficulty of study word processing. Despite evidence that relatively low visual contrast and relatively high visual background noise, in particular, create challenging conditions, we found no evidence that perceptual quality impacts the magnitude of the directed forgetting effect. This work suggests that data limitations have no discernible effect on forgetting and corroborate that only attentional resource limitations improve directed forgetting.


Sujet(s)
Rappel mnésique , , Attention , Signaux , Humains , Plan de recherche
11.
J Med Chem ; 64(3): 1454-1480, 2021 02 11.
Article de Anglais | MEDLINE | ID: mdl-33492963

RÉSUMÉ

Sphingosine-1-phosphate (S1P) binds to a family of sphingosine-1-phosphate G-protein-coupled receptors (S1P1-5). The interaction of S1P with these S1P receptors has a fundamental role in many physiological processes in the vascular and immune systems. Agonist-induced functional antagonism of S1P1 has been shown to result in lymphopenia. As a result, agonists of this type hold promise as therapeutics for autoimmune disorders. The previously disclosed differentiated S1P1 modulator BMS-986104 (1) exhibited improved preclinical cardiovascular and pulmonary safety profiles as compared to earlier full agonists of S1P1; however, it demonstrated a long pharmacokinetic half-life (T1/2 18 days) in the clinic and limited formation of the desired active phosphate metabolite. Optimization of this series through incorporation of olefins, ethers, thioethers, and glycols into the alkyl side chain afforded an opportunity to reduce the projected human T1/2 and improve the formation of the active phosphate metabolite while maintaining efficacy as well as the improved safety profile. These efforts led to the discovery of 12 and 24, each of which are highly potent, biased agonists of S1P1. These compounds not only exhibited shorter in vivo T1/2 in multiple species but are also projected to have significantly shorter T1/2 values in humans when compared to our first clinical candidate. In models of arthritis, treatment with 12 and 24 demonstrated robust efficacy.


Sujet(s)
Composés bicycliques pontés/synthèse chimique , Composés bicycliques pontés/pharmacologie , Proprotein convertases/effets des médicaments et des substances chimiques , Serine endopeptidases/effets des médicaments et des substances chimiques , Animaux , Arthrite expérimentale/traitement médicamenteux , Maladies auto-immunes/traitement médicamenteux , Biotransformation , Composés bicycliques pontés/effets indésirables , Liquide de lavage bronchoalvéolaire , Chimiotaxie des leucocytes/effets des médicaments et des substances chimiques , Évaluation préclinique de médicament , Période , Humains , Maladies pulmonaires/induit chimiquement , Maladies pulmonaires/anatomopathologie , Mâle , Myocytes cardiaques/effets des médicaments et des substances chimiques , Phosphorylation , Rats , Rats de lignée LEW , Relation structure-activité
12.
Atten Percept Psychophys ; 83(4): 1629-1651, 2021 May.
Article de Anglais | MEDLINE | ID: mdl-33409904

RÉSUMÉ

This study embedded attentional cues in the study phase of an item-method directed forgetting task. We used an unpredictive onset cue (Experiment 1), a predictive onset cue (Experiment 2), or a predictive central cue (Experiments 3-6) to direct attention to the left or right. In Experiments 1-5, this was followed by a pink or blue study word that required a speeded colour discrimination; in Experiment 6, it was followed by a pink or blue word or nonword that required a lexical decision. Each study word was followed by an instruction to Remember or Forget. A yes-no recognition test confirmed better recognition of to-be-remembered words than to-be-forgotten words; a cueing effect confirmed the effectiveness of predictive cues in allocating attentional resources. There was, however, no evidence that the directed forgetting effect differed for attended and unattended words: Encoding depends more on the memory intention formed after a study word has disappeared than on the availability of processing resources when that word first appears.


Sujet(s)
Intention , Rappel mnésique , Signaux , Humains , Mémoire ,
13.
ACS Med Chem Lett ; 11(11): 2195-2203, 2020 Nov 12.
Article de Anglais | MEDLINE | ID: mdl-33214829

RÉSUMÉ

Bruton's tyrosine kinase (BTK) has been shown to play a key role in the pathogenesis of autoimmunity. Therefore, the inhibition of the kinase activity of BTK with a small molecule inhibitor could offer a breakthrough in the clinical treatment of many autoimmune diseases. This Letter describes the discovery of BMS-986143 through systematic structure-activity relationship (SAR) development. This compound benefits from defined chirality derived from two rotationally stable atropisomeric axes, providing a potent and selective single atropisomer with desirable efficacy and tolerability profiles.

14.
PLoS One ; 15(11): e0241959, 2020.
Article de Anglais | MEDLINE | ID: mdl-33166373

RÉSUMÉ

The coronavirus disease 2019 (Covid-19) pandemic, caused by SARS-CoV-2, has resulted in a global testing supply shortage. In response, pooled testing has emerged as a promising strategy that can immediately increase testing capacity. In pooled sample testing, multiple samples are combined (or pooled) together and tested as a single unit. If the pool is positive, the individual samples can then be individually tested to identify the positive case(s). Here, we provide support for the adoption of sample pooling with the point-of-care Cepheid Xpert® Xpress SARS-CoV-2 molecular assay. Corroborating previous findings, the limit of detection of this assay was comparable to laboratory-developed reverse-transcription quantitative PCR SARS-CoV-2 tests, with observed detection below 100 copies/mL. The Xpert® Xpress assay detected SARS-CoV-2 after samples with minimum viral loads of 461 copies/mL were pooled in groups of six. Based on these data, we recommend the adoption of pooled testing with the Xpert® Xpress SARS-CoV-2 assay where warranted based on public health needs. The suggested number of samples per pool, or the pooling depth, is unique for each point-of-care testing site and can be determined by the positive test rates. To statistically determine appropriate pooling depth, we have calculated the pooling efficiency for numerous combinations of pool sizes and test rates. This information is included as a supplemental dataset that we encourage public health authorities to use as a guide to make recommendations that will maximize testing capacity and resource conservation.


Sujet(s)
Betacoronavirus/génétique , Infections à coronavirus/diagnostic , Pneumopathie virale/diagnostic , ARN viral/métabolisme , RT-PCR/méthodes , Betacoronavirus/isolement et purification , COVID-19 , Infections à coronavirus/virologie , Humains , Pandémies , Pneumopathie virale/virologie , Analyse sur le lieu d'intervention , ARN viral/génétique , Trousses de réactifs pour diagnostic , SARS-CoV-2 , Manipulation d'échantillons , Charge virale
15.
ACS Med Chem Lett ; 11(9): 1766-1772, 2020 Sep 10.
Article de Anglais | MEDLINE | ID: mdl-32944145

RÉSUMÉ

Efforts aimed at increasing the in vivo potency and reducing the elimination half-life of 1 and 2 led to the identification of aryl ether and thioether-derived bicyclic S1P1 differentiated modulators 3-6. The effects of analogs 3-6 on lymphocyte reduction in the rat (desired pharmacology) along with pulmonary- and cardiovascular-related effects (undesired pharmacology) are described. Optimization of the overall properties in the aryl ether series yielded 3d, and the predicted margin of safety against the cardiovascular effects of 3d would be large enough for human studies. Importantly, compared to 1 and 2, compound 3d had a better profile in both potency (ED50 < 0.05 mg/kg) and predicted human half-life (t 1/2 ∼ 5 days).

16.
Viruses ; 12(6)2020 06 10.
Article de Anglais | MEDLINE | ID: mdl-32532083

RÉSUMÉ

Next-generation sequencing (NGS)-based HIV drug resistance (HIVDR) assays outperform conventional Sanger sequencing in scalability, sensitivity, and quantitative detection of minority resistance variants. Thus far, HIVDR assays have been applied primarily in research but rarely in clinical settings. One main obstacle is the lack of standardized validation and performance evaluation systems that allow regulatory agencies to benchmark and accredit new assays for clinical use. By revisiting the existing principles for molecular assay validation, here we propose a new validation and performance evaluation system that helps to both qualitatively and quantitatively assess the performance of an NGS-based HIVDR assay. To accomplish this, we constructed a 70-specimen proficiency test panel that includes plasmid mixtures at known ratios, viral RNA from infectious clones, and anonymized clinical specimens. We developed assessment criteria and benchmarks for NGS-based HIVDR assays and used these to assess data from five separate MiSeq runs performed in two experienced HIVDR laboratories. This proposed platform may help to pave the way for the standardization of NGS HIVDR assay validation and performance evaluation strategies for accreditation and quality assurance purposes in both research and clinical settings.


Sujet(s)
Résistance virale aux médicaments , Infections à VIH/virologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/génétique , Séquençage nucléotidique à haut débit/méthodes , Agents antiVIH/pharmacologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/effets des médicaments et des substances chimiques , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/isolement et purification , Séquençage nucléotidique à haut débit/normes , Humains , ARN viral/génétique
17.
mBio ; 10(5)2019 10 22.
Article de Anglais | MEDLINE | ID: mdl-31641086

RÉSUMÉ

The 1918 influenza virus, subtype H1N1, was the causative agent of the most devastating pandemic in the history of infectious diseases. In vitro studies have confirmed that extreme virulence is an inherent property of this virus. Here, we utilized the macaque model for evaluating the efficacy of oseltamivir phosphate against the fully reconstructed 1918 influenza virus in a highly susceptible and relevant disease model. Our findings demonstrate that oseltamivir phosphate is effective in preventing severe disease in macaques but vulnerable to virus escape through emergence of resistant mutants, especially if given in a treatment regimen. Nevertheless, we conclude that oseltamivir would be highly beneficial to reduce the morbidity and mortality rates caused by a highly pathogenic influenza virus although it would be predicted that resistance would likely emerge with sustained use of the drug.IMPORTANCE Oseltamivir phosphate is used as a first line of defense in the event of an influenza pandemic prior to vaccine administration. Treatment failure through selection and replication of drug-resistant viruses is a known complication in the field and was also demonstrated in our study with spread of resistant 1918 influenza virus in multiple respiratory tissues. This emphasizes the importance of early treatment and the possibility that noncompliance may exacerbate treatment effectiveness. It also demonstrates the importance of implementing combination therapy and vaccination strategies as soon as possible in a pandemic situation.


Sujet(s)
Sous-type H1N1 du virus de la grippe A/effets des médicaments et des substances chimiques , Sous-type H1N1 du virus de la grippe A/pathogénicité , Infections à Orthomyxoviridae/traitement médicamenteux , Oséltamivir/usage thérapeutique , Animaux , Macaca , Infections à Orthomyxoviridae/virologie
18.
Can J Exp Psychol ; 73(4): 254-264, 2019 Dec.
Article de Anglais | MEDLINE | ID: mdl-31393154

RÉSUMÉ

The production effect is defined as better memory for items that were read aloud compared with items that were read silently. Quinlan and Taylor (2013) expanded the findings of the production effect by demonstrating that singing items produces even better recognition performance than reading aloud, and argued that this was due to enhanced relative distinctiveness. The current study tested three alternative accounts. In Experiment 1, we explored whether singing results in a larger production effect because it is deemed more bizarre than reading aloud. To address this, we tested a sample for whom singing does not seem bizarre: experienced singers. They also showed better recognition of items that were sung compared with those that were read aloud. In Experiment 2, we determined that singing appears to take longer than either reading aloud or reading silently; however, the possible effect of production time was further explored in Experiment 3. We did this by instructing participants to sing quickly, read aloud slowly, or read silently. Altering relative production times resulted in no discernible changes in subsequent recognition performance. Finally, in Experiment 4, we explored whether singing might strengthen the memory trace relative to reading aloud. We tested this by manipulating the production instruction between subjects. This eliminated the recognition advantage for both reading items aloud as well as for singing them aloud. Having ruled out these alternatives, we argue that singing improves subsequent recognition because it offers more distinctive elements than either reading aloud or reading silently. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Sujet(s)
Rappel mnésique/physiologie , Reconnaissance visuelle des formes/physiologie , Lecture , /physiologie , Chant/physiologie , Adulte , Humains , Jeune adulte
19.
Sci Rep ; 9(1): 8970, 2019 06 20.
Article de Anglais | MEDLINE | ID: mdl-31222149

RÉSUMÉ

Conventional HIV drug resistance (HIVDR) genotyping utilizes Sanger sequencing (SS) methods, which are limited by low data throughput and the inability of detecting low abundant drug resistant variants (LADRVs). Here we present a next generation sequencing (NGS)-based HIVDR typing platform that leverages the advantages of Illumina MiSeq and HyDRA Web. The platform consists of a fully validated sample processing protocol and HyDRA web, an open web portal that allows automated customizable NGS-based HIVDR data processing. This platform was characterized and validated using a panel of HIV-spiked plasma representing all major HIV-1 subtypes, pedigreed plasmids, HIVDR proficiency specimens and clinical specimens. All examined major HIV-1 subtypes were consistently amplified at viral loads of ≥1,000 copies/ml. The gross error rate of this platform was determined at 0.21%, and minor variations were reliably detected down to 0.50% in plasmid mixtures. All HIVDR mutations identifiable by SS were detected by the MiSeq-HyDRA protocol, while LADRVs at frequencies of 1~15% were detected by MiSeq-HyDRA only. As compared to SS approaches, the MiSeq-HyDRA platform has several notable advantages including reduced cost and labour, and increased sensitivity for LADRVs, making it suitable for routine HIVDR monitoring for both patient care and surveillance purposes.


Sujet(s)
Résistance virale aux médicaments , Génotype , Infections à VIH/épidémiologie , Infections à VIH/virologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/effets des médicaments et des substances chimiques , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/génétique , Gènes viraux , Infections à VIH/traitement médicamenteux , Séquençage nucléotidique à haut débit/méthodes , Humains , Mutation , Surveillance de la santé publique , ARN viral , Reproductibilité des résultats , Charge virale
20.
ACS Med Chem Lett ; 10(3): 383-388, 2019 Mar 14.
Article de Anglais | MEDLINE | ID: mdl-30891145

RÉSUMÉ

In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo-N1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-b]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure-activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor 6, which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.

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