A novel noble metal stent coating reduces in vitro platelet activation and acute in vivo thrombosis formation: a blinded study.

Inherent to any stenting procedure is the prescription of dual antiplatelet therapy (DAPT) to reduce the platelet response. Clinical guidelines recommend 6-12 months of DAPT, depending on stent type, clinical picture and patient factors. Our hypothesis is that a nanostructured noble metal coating has the potential to reduce protein deposition and platelet activation. These effects would reduce subsequent thrombo-inflammatory reactions, potentially mitigating the need for an extensive DAPT in the acute phase. Here, a noble metal nanostructure coating on stents is investigated. Twelve pigs underwent endovascular implantation of coated and non-coated stents for paired comparisons in a blinded study design. The non-coated control stent was placed at the contralateral corresponding artery. Volumetric analysis of angiographic data, performed by a treatment blinded assessor, demonstrated a significant thrombus reduction for one of the coatings compared to control. This effect was already seen one hour after implantation. This finding was supported by in vitro data showing a significant reduction of coagulation activation in the coated group. This novel coating shows promise as an implant material addition and could potentially decrease the need for DAPT in the early phases of stent implementation.

Partners' experiences of living with men who have screening-detected abdominal aortic aneurysms: A qualitative descriptive study.

AIM: To describe partners' experiences of living with men with a screening-detected abdominal aortic aneurysm (AAA). BACKGROUND: Diagnosis of a chronic life-threatening disease affects the patients' as well as their partners' lives in different aspects. AAA, with rupture as the major consequence, is a life-threatening disease that can affect the whole family. Screening programmes for AAA have been introduced in several countries to reduce the mortality rate. Although the awareness of having an AAA influences the individuals' quality of life and well-being, it is still unclear how it affects their partners. DESIGN: Qualitative descriptive design. METHODS: Twenty-one partners of men with AAA were purposely selected to participate in individual semi-structured interviews between August 2017-February 2018 in Sweden. Data were transcribed and imported into NVivo-12® . The data were analysed using qualitative content analysis. The study conforms to the COREQ checklist. RESULTS: Three categories were identified: (a) experiencing the unexpected; (b) being reminded of fragility; and (c) balancing a changing relationship. The partners had a positive attitude towards the screening process and were pleased that their husbands were under surveillance. Nevertheless, at the same time, the diagnosis caused worries and questions. The AAA diagnosis was constantly in the minds of the partners, which sometimes affected and limited daily activities. Furthermore, ambivalent feelings towards surgical treatment were described. The partners tried to support their men and encouraged them to achieve a healthy lifestyle. CONCLUSION: The partners' well-being and daily lives were impacted by the awareness of the screening-detected AAA. Different degrees of worry were the most common reaction and were pervasive in all three categories. RELEVANCE FOR CLINICAL PRACTICE: The result highlights the need to review routines or develop new strategies to include the partners in the process of screening and offer supplementary support and information.

Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor.

Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1.

Discovery and Optimization of Quinolinone Derivatives as Potent, Selective, and Orally Bioavailable Mutant Isocitrate Dehydrogenase 1 (mIDH1) Inhibitors.

Mutations at the arginine residue (R132) in isocitrate dehydrogenase 1 (IDH1) are frequently identified in various human cancers. Inhibition of mutant IDH1 (mIDH1) with small molecules has been clinically validated as a promising therapeutic treatment for acute myeloid leukemia and multiple solid tumors. Herein, we report the discovery and optimization of a series of quinolinones to provide potent and orally bioavailable mIDH1 inhibitors with selectivity over wild-type IDH1. The X-ray structure of an early lead 24 in complex with mIDH1-R132H shows that the inhibitor unexpectedly binds to an allosteric site. Efforts to improve the in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) properties of 24 yielded a preclinical candidate 63. The detailed preclinical ADME and pharmacology studies of 63 support further development of quinolinone-based mIDH1 inhibitors as therapeutic agents in human trials.

Impact on Quality of Life of Men with Screening-Detected Abdominal Aortic Aneurysms Attending Regular Follow ups: A Narrative Literature Review.

OBJECTIVE: This study aimed to review, summarise, and assess the available evidence regarding the impact on the quality of life (QoL) of men undergoing screening for abdominal aortic aneurysm (AAA) and attending regular follow ups. METHODS: PubMed, MEDLINE, CINAHL, and PsycINFO were used for searching. The search was performed from April to July 2016, with an update in February-March 2018. The quality of the studies was appraised with respective checklists from the Critical Appraisal Skills Programme. A narrative synthesis of the included studies was performed. The analysis included studies evaluating QoL in relation to one or more of the following concepts: physical function, psychological impact and social life in men undergoing AAA screening, but excluded studies evaluating QoL in AAA patients diagnosed outside a screening program. RESULTS: The initial results from the search were 128 articles. Duplicates were removed, titles and abstracts were screened, and 22 full text articles were collected. Based on the inclusion criteria, 11 quantitative studies were included. Inferior quality of life among men with detected AAA was identified compared to those without the diagnosis and the general population in the included studies. The self-perceived health decreased over time for the participants with AAA. Assessments after surgery showed that the participants returned to similar health as before the screening. A wide variety of factors regarding the methodologies, designs, measurements, sample sizes, and the time for the assessment were noted in the included studies. CONCLUSION: Quality of life is an important outcome for AAA screening and studies have been conducted in an attempt to address the imbalance between benefits and harm. However, it is still difficult to draw clear conclusions, possibly due to the heterogeneity of the original studies. Nevertheless, it is important to identify men with an AAA who develop conditions influencing their health and QoL in order to understand their care needs to further support them and improve their situation.

Patients' Experiences During Carotid Endarterectomy Performed Under Local Anesthesia.

PURPOSE: To describe patients' experiences undergoing a carotid endarterectomy (CEA) under local anesthesia. DESIGN: Explorative qualitative design. METHODS: Semistructured interviews with 15 participants who had undergone CEA under local anesthesia, analyzed by content analysis. FINDINGS: Undergoing CEA under local anesthesia entails enduring stress with no possibility of withdrawal. Patients' lack of understanding of local anesthesia and experiencing pain and discomfort caused feelings of stress. The surgery resulted in a loss of control; patients had to surrender their autonomy to someone else. The nurse anesthetist was the link to the world outside the operating room (OR), and that nurse conveyed feelings of safety and security during the surgery. CONCLUSIONS: Patients' experiences ranged from being pleased with the surgical procedure and local anesthesia to vowing never to undergo such a procedure again. It is important to focus on the patients' experiences and feelings when choosing a method of anesthesia.

Psychosocial consequences in men taking part in a national screening program for abdominal aortic aneurysm.

Screening for abdominal aortic aneurysm (AAA) has proven to reduce AAA-related mortality, but how the knowledge of having an untreated AAA affects health and daily life requires further clarification. The aim was to investigate the psychosocial consequences and sense of coherence (SOC) in 65-year-old men diagnosed with AAA and participating in a national screening program during a 6-month follow-up compared with men with no AAA. The single-center cohort study included 52 men with AAA and 118 men without AAA. A questionnaire including the Short Form 36 Health Survey, Hospital Anxiety and Depression Scale, SOC, questions concerning stress, and questions related to AAA were answered at baseline and after 6 months. Men with AAA reported more problems with physical functioning, pain, and general health than men with a normal aorta at baseline. After 6 months, men with AAA still reported more problems with physical functioning and stress in relation to disease than men with normal aortic diameter. No differences were observed between groups in SOC, anxiety, and depression. A significantly higher satisfaction with information from the physician and desire to learn about the AAA diagnosis was reported at baseline compared with that at follow-up. Having knowledge about the AAA diagnosis may moderately impact physical health and perceived stress, and in combination with the increased prevalence of other cardiovascular diseases, may lead to impaired perceived health for men diagnosed with AAA.

Effects of exercise on fatigue and physical capacity in men with chronic widespread pain - a pilot study.

BACKGROUND: There is very limited knowledge about the effects of exercise on men with Chronic Widespread Pain (CWP), especially regarding fatigue. We wanted to investigate the effects of resistance exercise compared with pool exercise on multidimensional fatigue, psychological distress and physical capacity in men with CWP. METHODS: Thirty-four men with CWP, with a mean age of 49 (SD 8, range 26-59) years, were randomised to 12 weeks of standardised pool exercise (PE) or resistance exercise (RE). The primary outcome was the Multidimensional Fatigue Inventory (MFI-20). Depression, anxiety, isometric force, pain and health-related quality of life were also assessed. RESULTS: No significant differences were found for changes in MFI-20 between the exercise groups. The RE group improved the isometric forces of right shoulder abduction (RE: ∆2.2 SD 1.5 N, PE: ∆0.6 SD 1.2 N, p = 0.009), right knee flexion (RE: ∆50, SD 50 N, PE: ∆-17, SD 71 N, p = 0.003) and left knee flexion (RE: ∆33 SD 39, PE: ∆-9 SD 52 N, p = 0.017) compared with the PE group. The drop-out rate was 29 % in the RE group and 18 % in the PE group. CONCLUSIONS: Both a resistance exercise programme and a pool exercise programme improved different dimensions of fatigue in men with CWP. There were no differences in the change in fatigue over time between the exercise groups. Resistance exercise improved isometric strength compared with pool exercise. Because different types of exercise appear to improve different aspects of health, the goals could guide the choice of treatment. Further exercise studies with larger groups are needed to gain more knowledge about the effect of exercise on fatigue in men with CWP. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01278641. Registration date April 2008.

Resistance exercise improves physical fatigue in women with fibromyalgia: a randomized controlled trial.

BACKGROUND: Fibromyalgia (FM) affects approximately 1-3 % of the general population. Fatigue limits the work ability and social life of patients with FM. A few studies of physical exercise have included measures of fatigue in FM, indicating that exercise can decrease fatigue levels. There is limited knowledge about the effects of resistance exercise on multiple dimensions of fatigue in FM. The present study is a sub-study of a multicenter randomized controlled trial in women with FM. The purpose of the present sub-study was to examine the effects of a person-centered progressive resistance exercise program on multiple dimensions of fatigue in women with FM, and to investigate predictors of the potential change in fatigue. METHODS: A total of 130 women with FM (age 22-64 years) were included in this assessor-blinded randomized controlled multicenter trial examining the effects of person-centered progressive resistance exercise compared with an active control group. The intervention was performed twice a week for 15 weeks. Outcomes were five dimensions of fatigue measured with the Multidimensional Fatigue Inventory (MFI-20). Information about background was collected and the women also completed several health-related questionnaires. Multiple linear stepwise regression was used to analyze predictors of change in fatigue in the total population. RESULTS: A higher improvement was found at the post-treatment examination for change in the resistance exercise group, as compared to change in the active control group in the MFI-20 subscale of physical fatigue (resistance group Δ -1.7, SD 4.3, controls Δ 0.0, SD 2.7, p = 0.013), with an effect size of 0.33. Sleep efficiency was the strongest predictor of change in the MFI-20 subscale general fatigue (beta = -0.54, p = 0.031, R (2) = 0.05). Participating in resistance exercise (beta = 1.90, p = 0.010) and working fewer hours per week (beta = 0.84, p = 0.005) were independent significant predictors of change in physical fatigue (R (2) = 0.14). CONCLUSIONS: Person-centered progressive resistance exercise improved physical fatigue in women with FM when compared to an active control group. TRIAL REGISTRATION: ClinicalTrials.gov NCT01226784 . Registered 21 October 2010.

How to manage fatigue in fibromyalgia: nonpharmacological options.

The aim of this article is to suggest recommendations for the management of fatigue in fibromyalgia (FM) by reviewing and compiling findings of nonpharmacological treatment for fatigue in patients with FM. The management of fatigue in FM should incorporate regular physical exercise maintained for a longer period of time, which contributes to improved general health and facilitates coping with fatigue and other symptoms. The evidence is still low and the effect of exercise on fatigue in FM needs to be further studied. Patients with FM appear to benefit from general sleep hygiene advice and also need to develop individual strategies to manage the complex factors in everyday life that may be related to fatigue.

Psychometric properties of the Stress and Crisis Inventory (SCI-93) in females with fibromyalgia and chronic widespread pain.

BACKGROUND: Fibromyalgia (FM) and chronic widespread pain (CWP) are commonly associated with symptoms such as fatigue, stiffness, tension, exhaustion and psychological distress. Research on biological markers of the degree of stress symptoms has been conducted for decades. However, biological markers do not offer sufficient information for clinical practice, and thus, validated rating scales are still the best assessment option. The Stress and Crisis Inventory-93 (SCI-93) was designed to assess the severity of symptoms that are primarily related to the autonomous nervous system. OBJECTIVE: The purpose of this study was to evaluate the psychometric properties of the SCI-93 with regard to known-group validity, internal consistency and test-retest reliability. METHODS: The study included 166 women with FM or CWP in addition to 157 age-matched healthy women. The test-retest reliability was investigated in 40 women with FM. RESULTS: A one-factor solution was chosen, which explained 53% of the total variance; Cronbach's alpha was 0.98. The group of patients with FM and CWP showed significantly higher SCI-93 total scores than the healthy reference group (mean = 76.4 ± 24.9 vs. mean = 24.9 ± 21.3; P < 0.001), supporting known-group validity. In the test-retest reliability study, the intra class correlation for the SCI-93 total score was 0.95. CONCLUSIONS: The SCI-93 demonstrated satisfactory known-group validity and test-retest reliability. The instrument appears to reflect well the severity of autonomous symptoms.

Usefulness of multiple dimensions of fatigue in fibromyalgia.

OBJECTIVES: To explore in which contexts ratings of multiple dimensions of fatigue are useful in fibromyalgia, and to compare multidimensional fatigue between women with fibromyalgia and healthy women. DESIGN: A cross-sectional study. SUBJECTS AND METHODS: The Multidimensional Fatigue Inventory (MFI-20), comprising 5 subscales of fatigue, was compared with the 1-dimensional subscale of fatigue from the Fibromyalgia Impact Questionnaire (FIQ) in 133 women with fibromyalgia (mean age 46 years; standard deviation 8.6), in association with socio-demographic and health-related aspects and analyses of explanatory variables of severe fatigue. The patients were also compared with 158 healthy women (mean age 45 years; standard deviation 9.1) for scores on MFI-20 and FIQ fatigue. RESULTS: The MFI-20 was associated with employment, physical activity and walking capacity (rs = -0.27 to -0.36), while FIQ fatigue was not. MFI-20 and FIQ fatigue were equally associated with pain, sleep, depression and anxiety (rs = 0.32-0.63). Regression analyses showed that the MFI-20 increased the explained variance (R2) for the models of pain intensity, sleep, depression and anxiety, by between 7 and 29 percentage points, compared with if FIQ fatigue alone was included in the models. Women with fibromyalgia rated their fatigue higher than healthy women for all subscales of the MFI-20 and the FIQ fatigue (p < 0.001). CONCLUSION: Dimensions of fatigue, assessed by the MFI-20, appear to be valuable in studies of employment, pain intensity, sleep, distress and physical function in women with fibromyalgia. The patients reported higher levels on all fatigue dimensions in comparison with healthy women.

Design and synthesis of tricyclic cores for kinase inhibition.

Interest in therapeutic kinase inhibitors continues to grow beyond success in oncology. To date, ATP-mimetic kinase inhibitors have focused primarily on monocyclic and bicyclic heterocyclic cores. We sought to expand on the repertoire of potential cores for kinase inhibition by exploring tricyclic variants of classical bicyclic hinge binding motifs such as pyrrolopyridine and pyrrolopyrazine. Herein we describe the syntheses of eight alternative tricyclic cores as well as in vitro screening results for representative kinases of potential therapeutic interest.

Thienopyrrole acetic acids as antagonists of the CRTH2 receptor.

The bioisosteric replacement of the indole core of CRTH2 antagonists using thienopyrroles was investigated, resulting in potent antagonists with good selectivity over DP1. Early ADME/PK assessment of this chemotype demonstrated bioavailability in mice.

2,4-Diaminopyrimidine MK2 inhibitors. Part I: Observation of an unexpected inhibitor binding mode.

MK2 is a Ser/Thr kinase of significant interest as an anti-inflammatory drug discovery target. Here we describe the development of in vitro tools for the identification and characterization of MK2 inhibitors, including validation of inhibitor interactions with the crystallography construct and determination of the unique binding mode of 2,4-diaminopyrimidine inhibitors in the MK2 active site. Use of these tools in the optimization of a potent and selective inhibitor lead series is described in the accompanying Letter.

2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization.

We describe structure-based optimization of a series of novel 2,4-diaminopyrimidine MK2 inhibitors. Co-crystal structures (see accompanying Letter) demonstrated a unique inhibitor binding mode. Resulting inhibitors had IC(50) values as low as 19nM and moderate selectivity against a kinase panel. Compounds 15, 31a, and 31b inhibit TNFalpha production in peripheral human monocytes.

Pool exercise for patients with fibromyalgia or chronic widespread pain: a randomized controlled trial and subgroup analyses.

OBJECTIVE: To evaluate the effects of pool exercise in patients with fibromyalgia and chronic widespread pain and to determine characteristics influencing the effects of treatment. METHODS: A total of 134 women with fibromyalgia and 32 with chronic widespread pain were randomized to a 20-session pool exercise and a 6-session education programme or to a control group undertaking the same education programme. The primary outcomes were the Fibromyalgia Impact Questionnaire (FIQ) total score and the 6-minute walk test (6MWT). FIQ Pain and other health variables were included. RESULTS: The FIQ total (p = 0.04) improved in the intervention group, with an effect size of 0.32. Patients who had participated in at least 60% of the exercise sessions improved in the FIQ total (effect size 0.44), the 6MWT (effect size 0.43) and FIQ Pain (effect size 0.69) compared with controls (p < 0.05). Long-term follow-up revealed lasting, but small, improvement (effect size < 0.29) in the 6MWT among the active participants (p < 0.05). Analyses within the subgroups showed that patients with milder stress, pain or depression improved most by treatment on the FIQ total (effect size > 0.50, p < 0.05) compared with controls. CONCLUSION: The exercise-education programme showed significant, but small, improvement in health status in patients with fibromyalgia and chronic widespread pain, compared with education only. Patients with milder symptoms improved most with this treatment.

Synthesis and in vitro activity of N'-cyano-4-(2-phenylacetyl)-N-o-tolylpiperazine-1-carboximidamide P2X7 antagonists.

A novel series of cyanoguanidine-piperazine P2X(7) antagonists was designed based upon the structure of A-740003. Structure-activity relationship (SAR) studies focused on the piperazine moiety and the right hand side substitution. Compounds were assayed for activity at human and rat P2X(7) receptors and compound 29 was found to possess potent activity (IC(50)=30-60 nM) at both species.

Experience of physical activity in patients with fibromyalgia and chronic widespread pain.

PURPOSE: Patients with fibromyalgia (FM) and chronic widespread pain (CWP) find physical activity troublesome. The purpose was to develop a questionnaire to investigate the experience of physical activity in FM and CWP populations. METHOD: A questionnaire was developed from a qualitative study. After that, a total of 204 patients with FM or CWP completed the questionnaire. A factor analysis was conducted and the internal consistency was investigated. The relationship between the factors and pain, health status (the Fibromyalgia Impact Questionnaire, FIQ), distress (the Hospital Anxiety and Distress scale, HAD) and leisure time physical activity (the Leisure Time Physical Activity Instrument, LTPAI) was investigated. RESULTS: Five factors were identified: Physical Relaxation (PR), Well-being (WB), Activity Beliefs (AB), Activity-related Symptoms (AS) and Activity Habits (AH). Cronbach's alpha ranged from 0.57 to 0.86. The PR showed a correlation (rho 0.28, p < 0.01) with the FIQ Pain. The AS showed a correlation (rho 0.25, p < 0.01) with the FIQ total score, while the AH showed a correlation with the HAD Depression (0.26, p < 0.01) and with strenuous physical activity (LTPAI) (-0.32, p < 0.01). CONCLUSION: A new instrument was developed to study the experience of physical activity in persons with long-lasting pain. Five factors were identified using factor analysis, and three of them showed fair associations with FM symptoms, distress or physical activity.

Assessment of fatigue in patients with fibromyalgia and chronic widespread pain. Reliability and validity of the Swedish version of the MFI-20.

OBJECTIVES: Fibromyalgia (FM) and Chronic Widespread Pain (CWP) are common diseases in primary care and, in addition to the pain they cause, fatigue is a major problem. Fatigue is regarded as a multidimensional concept and instruments assessing fatigue should therefore cover several different dimensions. The Multidimensional Fatigue Inventory (MFI-20) measures five different dimensions of fatigue. The aim of the study was to investigate the test-retest reliability and convergent construct validity of the Swedish version of the MFI-20 in female patients with FM or CWP. METHODS: To investigate the convergent construct validity, 166 female patients with FM or CWP completed the Swedish version of the MFI-20 and a Visual Analogue Scale (VAS) measuring global fatigue. Thirty-six of the 166 patients completed the Swedish version of the MFI-20 on two occasions, one day apart to evaluate the test-retest reliability. RESULTS: Spearman's correlation coefficient revealed a significant association between each of the five subscales of the MFI-20 and the VAS for global fatigue. General Fatigue had the highest correlation with the VAS (rs = 0.62, p < 0.001), while Reduced Motivation had the lowest (rs = 0.32, p <0.001). The intra-class correlation coefficients (ICC) were satisfactory for all the five subscales of the MFI-20. CONCLUSION: The results of this study indicate that the Swedish version of the MFI-20 is a reliable tool for assessing the degree of fatigue in patients with FM or CWP. This study also supports the theory that fatigue is a multidimensional concept and different aspects of fatigue should be measured separately.