EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor

ACKNOWLEDGEMENTS We thank J. M. Valverde (IRB) as well as the NMR facilities of the University of Barcelona (CCiT UB) and the Instituto de Química Física Rocasolano (IQFR, CSIC) for their assistance in, respectively, protein production and NMR. This work was supported by IRB, ICREA (X.S.), Obra Social “la Caixa” (Fellowship to E.D.M. and CancerTec grants to X.S.) MICINN (CTQ2009-08850 to X.S.), MINECO (BIO2012-31043 to X.S.; CTQ2014-56361-P to A.R), Marató de TV3 (102030 to X.S. and 102031 to E.E.P) the COFUND programme of the European Commission (C.T.W.P., A. R. and X.S.), the European Research Council (CONCERT, contract number 648201, to X.S.), the Ramón y Cajal program of MICINN (RYC-2011-07873 to C.W.B.) the Serra Hunter Programme (E.E.P.) and AGAUR (SGR-2014-56RR14 to E.E.P). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain)Peer reviewedPostprin

Identifying Content for the Glaucoma-specific Item Bank to Measure Quality-of-life Parameters

"This is a non-final version of an article published in final form in Khadka J, McAlinden C, Craig JE, Fenwick EK, Lamoureux EL, Pesudovs K. Identifying content for the glaucoma-specific item bank to measure quality-of-life parameters. Journal of Glaucoma . 2015 Jan;24(1):12-9. doi: 10.1097/IJG.0b013e318287ac11.". Author manuscript version made available in accordance with publisher copyright policy.PURPOSE: Patient-reported outcomes (PROs) have become essential clinical trial end points. However, a comprehensive, multidimensional, patient-relevant, and precise glaucoma-specific PRO instrument is not available. Therefore, the purpose of this study was to identify content for a new, glaucoma-specific, quality-of-life (QOL) item bank. METHODS: Content identification was undertaken in 5 phases: (1) identification of extant items in glaucoma-specific instruments and the qualitative literature; (2) focus groups and interviews with glaucoma patients; (3) item classification and selection; (4) expert review and revision of items; and (5) cognitive interviews with patients. RESULTS: A total of 737 unique items (extant items from PRO instruments, 247; qualitative articles, 14 items; focus groups and semistructured interviews, 476 items) were identified. These items were classified into 10 QOL domains. Four criteria (item redundancy, item inconsistent with domain definition, item content too narrow to have wider applicability, and item clarity) were used to remove and refine the items. After the cognitive interviews, the final minimally representative item set had a total of 342 unique items belonging to 10 domains: activity limitation (88), mobility (20), visual symptoms (19), ocular surface symptoms (22), general symptoms (15), convenience (39), health concerns (45), emotional well-being (49), social issues (23), and economic issues (22). CONCLUSIONS: The systematic content identification process identified 10 QOL domains, which were important to patients with glaucoma. The majority of the items were identified from the patient-specific focus groups and semistructured interviews suggesting that the existing PRO instruments do not adequately address QOL issues relevant to individuals with glaucoma

Illness Cognitions and Coping Self-Efficacy in Depression Among Persons With Low Vision.

PURPOSE: To investigate the mediating role of coping self-efficacy (CSE) between two types of illness cognitions (i.e., acceptance and helplessness) and depressive symptoms in persons with low vision. METHODS: This was a single-group, cross-sectional study. Patients with visual acuity \u3c 6/12 in the better eye and at least minimal depressive symptoms (≥5 on the Patient Health Questionnaire-9 [PHQ-9]) were recruited from vision rehabilitation services and participated in telephone-administered structured interviews at one time point. Measures were the PHQ-9, CSE Scale, and Illness Cognition Questionnaire. Structural equation modeling (SEM) devised the causal flow of illness cognitions and their observed indirect effects on depressive symptoms via the CSE mediators: problem focused, emotion focused, and social support. RESULTS: The study comprised 163 patients (mean age 62 years; 61% female), most with age-related macular degeneration (26%) and moderate vision impairment (44%, \u3c6/18-6/60). Structural equation modeling indices indicated a perfect fit (χ2 \u3c 0.001, P = 1.00), accounting for 55% of the variance in depressive symptoms. Lower levels of acceptance and higher levels of helplessness illness cognitions were associated with lower self-efficacy in problem-focused coping (β = 0.38, P \u3c 0.001, β = -0.28, P \u3c 0.01, respectively), which in turn was associated with greater depressive symptom severity (β = -0.54, P \u3c 0.001). CONCLUSIONS: Lack of acceptance and greater helplessness relating to low vision led to a lack of perceived capability to engage in problem-focused coping, which in turn promoted depressive symptoms. Third-wave cognitive-behavioral treatments that focus on acceptance may be efficacious in this population

The impact of successful cataract surgery on quality of life, household income and social status in South India.

BACKGROUND: To explore the hypothesis that sight restoring cataract surgery provided to impoverished rural communities will improve not only visual acuity and vision-related quality of life (VRQoL) but also poverty and social status. METHODS: Participants were recruited at outreach camps in Tamil Nadu, South India, and underwent free routine manual small incision cataract surgery (SICS) with intra-ocular lens (IOL) implantation, and were followed up one year later. Poverty was measured as monthly household income, being engaged in income generating activities and number of working household members. Social status was measured as rates of re-marriage amongst widowed participants. VRQoL was measured using the IND-VFQ-33. Associations were explored using logistic regression (SPSS 19). RESULTS: Of the 294 participants, mean age ± standard deviation (SD) 60 ± 8 years, 54% men, only 11% remained vision impaired at follow up (67% at baseline; p<0.001). At one year, more participants were engaged in income generating activities (44.7% to 77.7%; p<0.001) and the proportion of households with a monthly income <1000 Rps. decreased from 50.5% to 20.5% (p<0.05). Overall VRQoL improved (p<0.001). Participants who had successful cataract surgery were less likely to remain in the lower categories of monthly household income (OR 0.05-0.22; p<0.02) and more likely to be engaged in income earning activities one year after surgery (OR 3.28; p = 0.006). Participants widowed at baseline who had successful cataract surgery were less likely to remain widowed at one year (OR 0.02; p = 0.008). CONCLUSION: These findings indicate the broad positive impact of sight restoring cataract surgery on the recipients' as well as their families' lives. Providing free high quality cataract surgery to marginalized rural communities will not only alleviate avoidable blindness but also - to some extent - poverty in the long run

The relative impact of vision impairment and cardiovascular disease on quality of life: the example of pseudoxanthoma elasticum

<p>Abstract</p> <p>Objective</p> <p>To investigate the impact of pseudoxanthoma elasticum (PXE), a rare hereditary disease of concurrent vision impairment (VI) and cardiovascular complications (CVCs), on vision-related (VRQoL) and health-related quality of life (HRQoL).</p> <p>Methods</p> <p>VRQoL and HRQoL were assessed using the Impact of Vision Impairment (IVI) questionnaire and the Short Form Health Survey (SF-36) in 107 PXE patients. Patients were stratified into four groups: A = no VI or CVC; B = CVCs only; C = VI only; and D = both VI and CVCs.</p> <p>Results</p> <p>Following Rasch analysis, the IVI was found to function as a vision-specific functioning and emotional well-being subscale, and the SF-36 as a health-related physical functioning and mental health subscale. The presence of VI and CVC were significant predictors of vision-specific functioning and emotional well-being (p < 0.001), with a clinically meaningful decrement in vision-specific functioning in patients with VI. No associations were found for the SF-36 Physical Functioning and Mental Health scores between any groups.</p> <p>Conclusions</p> <p>Vision impaired patients with PXE report significantly poorer vision-specific functioning than PXE patients without VI. In contrast, the relative impact of PXE on reported general HRQoL was much less. Our results suggest that vision impairment has the larger impact on QoL in this sample.</p

Sociomateriality in medical practice and learning: Attuning to what matters

CONTEXT In current debates about professional practice, learning and education, increasing emphasis is being placed on understanding learning as ongoing participation rather than as acquiring knowledge and skills. Close attention is paid to the sociocultural context as well as to cognition. While this general sociocultural view is important and useful, issues have emerged in studies of practice-based learning that point to certain oversights. METHOD Three issues are described here: (1) the general lack of attention to the importance of materiality &ndash; objects, technologies, nature etc &ndash; in questions of learning; (2) the human-centric view of challenges and complexities in practice that fail to note the transformational entanglements among social and material forces; and (3) the conflicts between ideals of evidence-based standardized models and the sociomaterial contingencies of clinical practice.&nbsp; &nbsp; DISCUSSION It is argued here that a sociomaterial approach to learning and practice offers important insights for medical education. This view joins a growing field of research in the materiality of practice and everyday life, which embraces wide-ranging theoretical families that can only be briefly mentioned in this short introduction. The main premise they share is that social and material forces, culture, nature and technology, are enmeshed in everyday practice. Objects and humans act upon one another in ways that mutually transform their characteristics and activity. Examples from research in medical practice show how materials actively influence clinical practice, how learning itself is a material matter, how protocols are in fact temporary sociomaterial achievements, and how practices form unique and sometimes conflicting sociomaterial worlds, with diverse diagnostic and treatment approaches for the same thing. &nbsp; CONCLUSIONS The article concludes with implications for learning in practice. The shift is from sole emphasis on acquiring knowledge representations to learning how to participate more wisely in particular situations. Focus is on learning how to attune to minor material fluctuations and surprises, how to track one&rsquo;s own and other&rsquo;s effects on the &lsquo;intra-actions&rsquo; and emerging effects, and how to improvise solutions

EPI-001, a compound active against castration-resistant prostate cancer, targets transactivation unit 5 of the androgen receptor

Castration-resistant prostate cancer is the lethal condition suffered by prostate cancer patients that become refractory to androgen deprivation therapy. EPI-001 is a recently identified compound active against this condition that modulates the activity of the androgen receptor, a nuclear receptor that is essential for disease progression. The mechanism by which this compound exerts its inhibitory activity is however not yet fully understood. Here we show, by using high resolution solution nuclear magnetic resonance spectroscopy, that EPI-001 selectively interacts with a partially folded region of the transactivation domain of the androgen receptor, known as transactivation unit 5, that is key for the ability of prostate cells to proliferate in the absence of androgens, a distinctive feature of castration-resistant prostate cancer. Our results can contribute to the development of more potent and less toxic novel androgen receptor antagonists for treating this disease

Evaluating empowerment in genetic counseling using patient-reported outcomes

Data about patient reported outcomes from cancer genetics services (CGS) are lacking but are essential to guide service evaluation and improvements. We measured improvement in empowerment, following genetic counseling in Singapore using a culturally‐adapted version of the Genetic Counseling Outcome Scale (GCOS‐24); and sought to identify factors associated with change in empowerment. The GCOS‐24 was administered to 155 patients of the CGS, at pre‐ and post‐counseling or testing timepoints. Of which, 110 patients underwent genetic testing. Individual pre‐ and post‐counseling responses were subjected to Rasch analysis; the scale was subsequently split into cognitive control (CC) and emotional control (EC) domains. Associations of baseline characteristics with changes in pre‐ and post‐CC and EC scores were assessed using multiple regression analysis. Both CC and EC scores showed significant improvement following genetic counseling and testing. While all items in the CC domain of being showed increases at follow‐up, aspects of EC related to alleviating negative emotions (P = .88) and hopelessness (P = .2) did not show significant improvement. Our study revealed significant improvement in empowerment in patients who have received cancer genetic counseling, while revealing a need to cultivate hope and facilitate the alleviation of negative emotions in patients during genetic counseling

Is Sensory Loss an Understudied Risk Factor for Frailty? A Systematic Review and Meta-analysis

[Abstract] Background. Age-related sensory loss and frailty are common conditions among older adults, but epidemiologic research on their possible links has been inconclusive. Clarifying this relationship is important because sensory loss may be a clinically relevant risk factor for frailty. Methods. In this systematic review and meta-analysis, we searched 3 databases for observational studies investigating 4 sensory impairments—vision (VI), hearing (HI), smell (SI), and taste (TI)—and their relationships with frailty. We meta-analyzed the cross-sectional associations of VI/HI each with pre-frailty and frailty, investigated sources of heterogeneity using meta-regression and subgroup analyses, and assessed publication bias using Egger’s test. Results. We included 17 cross-sectional and 7 longitudinal studies in our review (N = 34,085) from 766 records. Our cross-sectional meta-analyses found that HI and VI were, respectively, associated with 1.5- to 2-fold greater odds of pre-frailty and 2.5- to 3-fold greater odds of frailty. Our results remained largely unchanged after subgroup analyses and meta-regression, though the association between HI and pre-frailty was no longer significant in 2 subgroups which lacked sufficient studies. We did not detect publication bias. Longitudinal studies largely found positive associations between VI/HI and frailty progression from baseline robustness, though they were inconclusive about frailty progression from baseline pre-frailty. Sparse literature and heterogenous methods precluded meta-analyses and conclusions on the SI/TI–frailty relationships. Conclusions. Our meta-analyses demonstrate significant cross-sectional associations between VI/HI with pre-frailty and frailty. Our review also highlights knowledge gaps on the directionality and modifiability of these relationships and the impact of SI/TI and multiple sensory impairments on frailty

The synergistic action of imidacloprid and flumethrin and their release kinetics from collars applied for ectoparasite control in dogs and cats

<p>Abstract</p> <p>Background</p> <p>The control of tick and flea burdens in dogs and cats has become essential to the control of important and emerging vector borne diseases, some of which are zoonoses. Flea worry and flea bite hypersensitivity are additionally a significant disease entity in dogs and cats. Owner compliance in maintaining the pressure of control measures has been shown to be poor. For these reasons efforts are continuously being made to develop ectoparasiticides and application methods that are safe, effective and easy to apply for pet owners. A new polymer matrix collar has recently been developed which is registered for 8 months use in cats and dogs. The basic properties of this collar have been investigated in several <it>in vitro </it>and <it>in vivo </it>studies.</p> <p>Methods</p> <p>The effects of imidacloprid, flumethrin and the combination were evaluated in vitro by means of whole cell voltage clamp measurement experiments conducted on isolated neuron cells from <it>Spodoptera frugiperda</it>. The in vitro efficacy of the two compounds and the combination against three species of ticks and their life stages and fleas were evaluated in a dry surface glass vial assay. The kinetics of the compounds over time in the collar were evaluated by the change in mass of the collar and measurement of the surface concentrations and concentrations of the actives in the collar matrix by HPLC. Hair clipped from collar treated dogs and cats, collected at various time points, was used to assess the acaricidal efficacy of the actives ex vivo.</p> <p>Results</p> <p>An <it>in vitro </it>isolated insect nerve model demonstrated the synergistic neurotoxic effects of the pyrethroid flumethrin and the neonicotinoid imidacloprid. An <it>in vitro </it>glass vial efficacy and mortality study against various life stages of the ticks <it>Ixodes ricinus, Rhipicephalus sanguineus </it>and <it>Dermacentor reticulatus </it>and against the flea (<it>Ctenocephalides felis</it>) demonstrated that the combination of these products was highly effective against these parasites. The release kinetics of these actives from a neck collar (compounded with 10% imidacloprid and 4.5% flumethrin) was extensively studied in dogs and cats under laboratory and field conditions. Acaricidal concentrations of the actives were found to be consistently released from the collar matrix for 8 months. None of the collar studies in dogs or cats were associated with any significant collar related adverse event.</p> <p>Conclusion</p> <p>Here we demonstrated the synergism between the pyrethroid flumethrin and the neonicotinoid imidacloprid, both provided in therapeutically relevant doses by a slow release collar matrix system over 8 months. This collar is therefore a convenient and safe tool for a long-term protection against ectoparasites.</p