Treatment Preferences of Adult Patients with Attention-Deficit/Hyperactivity Disorder – A Discrete Choice Experiment

Jeff Schein,1 Martin Cloutier,2 Marjolaine Gauthier-Loiselle,2 Maryaline Catillon,3 Yan Meng,4 Beatrice Libchaber,2 Fanny Jiang,2 Ann Childress5 1Otsuka Pharmaceutical Development & Commercialization, Inc, Princeton, NJ, USA; 2Analysis Group, Inc, Montréal, QC, Canada; 3Analysis Group, Inc, New York, NY, USA; 4Analysis Group, Inc, London, UK; 5Center for Psychiatry and Behavioral Medicine, Las Vegas, NV, USACorrespondence: Maryaline Catillon, Analysis Group, Inc, 151 West 42nd Street, 23rd Floor, New York, NY, 10036, USA, Tel +1 857 222 6863, Email [email protected]: Understanding patient preferences for treatments may facilitate shared decision-making. This study assessed adult patient preferences for attention-deficit/hyperactivity disorder (ADHD) treatments in a sample of 600 patients in the United States (US).Methods: A web-based discrete choice experiment (DCE) survey was conducted among treated adults with ADHD. Participants were recruited from Dynata’s US panel (06/22/2023-07/06/2023). Attributes and levels, identified based on clinical inputs and published data, included efficacy and safety. Participants’ preferences were estimated using conditional logistic regression. Willingness to trade-off and attributes’ relative importance were calculated. Overall preferences for treatment profiles approximating centanafadine, lisdexamfetamine, atomoxetine, and viloxazine were estimated using adjusted total utilities. Results were stratified by current treatment status. Sensitivity analyses including participants who passed validity tests were conducted.Results: Among the 600 participants (mean age 37.9 years; 66.2% female; 50.8% treated), all attributes had a statistically significant impact on preferences for ADHD treatments (p 60% of relative importance in decision-making. Participants were willing to forgo 0.59, 0.57, 0.49, 0.32, and 0.17 percentage points of symptom improvement to achieve one-percentage-point reduced risk of insomnia, nausea, anxiety, feeling jittery, and dry mouth, respectively. Centanafadine profile had consistently higher adjusted total utilities than its comparators. Similar results were obtained in the subgroup and sensitivity analyses.Conclusion: Efficacy was the most important attribute for patients when making treatment decision, but taken together, AEs had greater relative importance than efficacy alone. Accordingly, a profile resembling that of centanafadine would be preferred by an average patient compared to key competitors due to its favorable safety profile. These findings may help improve treatment decision-making, enhance treatment satisfaction, and foster adherence.Keywords: ADHD, decision-making, discrete choice experiment, patient-centered care, patient satisfaction, patient preference, utilit

Narrow genetic base in forest restoration with holm oak (Quercus ilex L.) in Sicily

In order to empirically assess the effect of actual seed sampling strategy on genetic diversity of holm oak (Quercus ilex) forestations in Sicily, we have analysed the genetic composition of two seedling lots (nursery stock and plantation) and their known natural seed origin stand by means of six nuclear microsatellite loci. Significant reduction in genetic diversity and significant difference in genetic composition of the seedling lots compared to the seed origin stand were detected. The female and the total effective number of parents were quantified by means of maternity assignment of seedlings and temporal changes in allele frequencies. Extremely low effective maternity numbers were estimated (Nfe $\approx$ 2-4) and estimates accounting for both seed and pollen donors gave also low values (Ne $\approx$ 35-50). These values can be explained by an inappropriate forestry seed harvest strategy limited to a small number of spatially close trees

The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding

The ability of Heat Shock Protein 90 (Hsp90) to hydrolyze ATP is essential for its chaperone function. The co-chaperone Aha1 stimulates Hsp90 ATPase activity, tailoring the chaperone function to specific "client" proteins. The intracellular signaling mechanisms directly regulating Aha1 association with Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability. FNIPs compete with the activating co-chaperone Aha1 for binding to Hsp90, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins. Lastly, downregulation of FNIPs desensitizes cancer cells to Hsp90 inhibitors, whereas FNIPs overexpression in renal tumours compared with adjacent normal tissues correlates with enhanced binding of Hsp90 to its inhibitors. Our findings suggest that FNIPs expression can potentially serve as a predictive indicator of tumour response to Hsp90 inhibitors

Ecological implications of a flower size/number trade-off in tropical forest trees

Peer reviewedPublisher PD

Basin-Scale Control on the Phytoplankton Biomass in Lake Victoria, Africa

The relative bio-optical variability within Lake Victoria was analyzed through the spatio-temporal decomposition of a 1997–2004 dataset of remotely-sensed reflectance ratios in the visible spectral range. Results show a regular seasonal pattern with a phase shift (around 2 months) between the south and north parts of the lake. Interannual trends suggested a teleconnection between the lake dynamics and El-Niño phenomena. Both seasonal and interannual patterns were associated to conditions of light limitation for phytoplankton growth and basin-scale hydrodynamics on phytoplankton access to light. Phytoplankton blooms developed during the periods of lake surface warming and water column stability. The temporal shift apparent in the bio-optical seasonal cycles was related to the differential cooling of the lake surface by southeastern monsoon winds. North-south differences in the exposure to trade winds are supported by the orography of the Eastern Great Rift Valley. The result is that surface layer warming begins in the northern part of the lake while the formation of cool and dense water continues in the southern part. The resulting buoyancy field is sufficient to induce a lake-wide convective circulation and the tilting of the isotherms along the north-south axis. Once surface warming spreads over the whole lake, the phytoplankton bloom dynamics are subjected to the internal seiche derived from the relaxation of thermocline tilting. In 1997–98, El-Niño phenomenon weakened the monsoon wind flow which led to an increase in water column stability and a higher phytoplankton optical signal throughout the lake. This suggests that phytoplankton response to expected climate scenarios will be opposite to that proposed for nutrient-limited great lakes. The present analysis of remotely-sensed bio-optical properties in combination with environmental data provides a novel basin-scale framework for research and management strategies in Lake Victoria

Computational Modelling of Cardiac Trabecula Mechanics

Cardiac trabeculae are thin strips of muscle within the ventricles that can be readily excised and used to investigate contractile mechanics of cardiac muscle. Recently, the Auckland Bioengineering Institute has developed a novel cardiac myometer that simultaneously measures force, length and shape of actively contracting isolated cardiac trabeculae. Here we have developed a muscle-specific computational model based on optical coherence tomography geometric surface data that replicates passive mechanics of trabecula. We hypothesised that the muscle's surface geometry data, in addition to force-length data, would improve the fit between the model simulated mechanics and the experimental data. The trabecula model was optimised using two different objective functions (muscle length or shape) driven by a pressure boundary condition. For both objective functions, there was a region of optimal parameters the optimiser tended towards but, due to the coupling between parameters, the ability to find the true optimal parameters was hindered. Due to the limitations of the data, we found that the addition of surface data did not improve parameter estimation and that using only the force-length data provided sufficient information to produce an optimal fit. References A. Anderson. The Cardiac Myometer: Measuring Matters of the Heart. PhD thesis, University of Auckland, 2016. K. F. Augenstein, Brett R. Cowan, Ian J. LeGrice, Poul M. F. Nielsen, and Alistair A. Young. Method and apparatus for soft tissue material parameter estimation using tissue tagged Magnetic Resonance Imaging. Journal of Biomechanical Engineering, 127(1):148–157, February 2005. C. Bradley, Andy Bowery, Randall Britten, Vincent Budelmann, Oscar Camara, Richard Christie, Andrew Cookson, Alejandro F. Frangi, Thiranja Babarenda Gamage, Thomas Heidlauf, Sebastian Krittian, David Ladd, Caton Little, Kumar Mithraratne, Martyn Nash, David Nickerson, Poul Nielsen, Oyvind Nordbo, Stig Omholt, Ali Pashaei, David Paterson, Vijayaraghavan Rajagopal, Adam Reeve, Oliver Rohrle, Soroush Safaei, Rafael Sebastian, Martin Steghofer, Tim Wu, Ting Yu, Heye Zhang, and Peter Hunter. OpenCMISS: A multi-physics and multi-scale computational infrastructure for the VPH/Physiome project. Progress in Biophysics and Molecular Biology, 107(1):32–47, October 2011. doi:http://dx.doi.org/10.1016/j.pbiomolbio.2011.06.015 M. L. Cheuk, A. J. Anderson, J. C. Han, N. Lippok, F. Vanholsbeeck, B. P. Ruddy, D. S. Loiselle, P. M. F. Nielsen, and A. J. Taberner. Four-Dimensional Imaging of Cardiac Trabeculae Contracting In Vitro Using Gated OCT. IEEE Transactions on Biomedical Engineering, 64(1):218–224, January 2017. doi:http://dx.doi.org/10.1109/TBME.2016.2553154 M. L. Cheuk, N. Lippok, A. W. Dixon, B. P. Ruddy, F. Vanholsbeeck, P. M. F. Nielsen, and A. J. Taberner. Optical coherence tomography imaging of cardiac trabeculae. In 2014 36th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, pages 182–185, August 2014. doi:http://dx.doi.org/10.1109/EMBC.2014.6943559 J. M Guccione, Andrew D McCulloch, and LK Waldman. Passive material properties of intact ventricular myocardium determined from a cylindrical model. J Biomech Eng, 113(1):42–55, 1991. J. C. Han, Andrew J. Taberner, Robert S. Kirton, Poul M. Nielsen, Nicholas P. Smith, and Denis S. Loiselle. A unique micromechanocalorimeter for simultaneous measurement of heat rate and force production of cardiac trabeculae carneae. Journal of Applied Physiology, 107(3):946–951, September 2009. doi:http://dx.doi.org/10.1152/japplphysiol.00549.2009 M. P. Nash and P. J. Hunter. Regional mechanics of the beating heart. In Cardiac Perfusion and Pumping Engineering, volume Volume 1 of Clinically-Oriented Biomedical Engineering, pages 83–127. WORLD SCIENTIFIC, July 2007. doi:http://dx.doi.org/10.1142/9789812775597_0004 J. H. Omens, D. A. MacKenna, and A. D. McCulloch. Measurement of strain and analysis of stress in resting rat left ventricular myocardium. Journal of Biomechanics, 26(6):665–676, June 1993. doi:http://dx.doi.org/10.1016/0021-9290(93)90030-I V. Y. Wang, H. I. Lam, Daniel B. Ennis, Brett R. Cowan, Alistair A. Young, and Martyn P. Nash. Modelling passive diastolic mechanics with quantitative MRI of cardiac structure and function. Medical Image Analysis, 13(5):773–784, October 2009. doi:http://dx.doi.org/10.1016/j.media.2009.07.00

Advancing an interdisciplinary framework to study seed dispersal ecology

Although dispersal is generally viewed as a crucial determinant for the fitness of any organism, our understanding of its role in the persistence and spread of plant populations remains incomplete. Generalizing and predicting dispersal processes are challenging due to context dependence of seed dispersal, environmental heterogeneity and interdependent processes occurring over multiple spatial and temporal scales. Current population models often use simple phenomenological descriptions of dispersal processes, limiting their ability to examine the role of population persistence and spread, especially under global change. To move seed dispersal ecology forward, we need to evaluate the impact of any single seed dispersal event within the full spatial and temporal context of a plant’s life history and environmental variability that ultimately influences a population’s ability to persist and spread. In this perspective, we provide guidance on integrating empirical and theoretical approaches that account for the context dependency of seed dispersal to improve our ability to generalize and predict the consequences of dispersal, and its anthropogenic alteration, across systems. We synthesize suitable theoretical frameworks for this work and discuss concepts, approaches and available data from diverse subdisciplines to help operationalize concepts, highlight recent breakthroughs across research areas and discuss ongoing challenges and open questions. We address knowledge gaps in the movement ecology of seeds and the integration of dispersal and demography that could benefit from such a synthesis. With an interdisciplinary perspective, we will be able to better understand how global change will impact seed dispersal processes, and potential cascading effects on plant population persistence, spread and biodiversity

Differential Regulation of PDE5 Expression in Left and Right Ventricles of Feline Hypertrophy Models

Though long known to affect smooth muscle biology, recent studies indicate that phosphodiesterase 5 (PDE5) is also expressed in myocardium. Recognizing that the regulation of PDE5 in hypertrophy is not well understood, we assessed the response of PDE5 expression and the level of cGMP-dependent kinase I (cGKI) in the left and right ventricles of feline hypertrophy models.Using a cDNA library of feline aortic smooth muscle cells, we identified and cloned PDE5 cDNA for the first time in this species. The sequence shares 98% identity with its human orthologue at the amino acid level. E. coli expression of the cloned allele allowed selection of antibodies with appropriate specificity, facilitating the analysis of PDE5 expression in feline models created by selective proximal aortic (Ao) or pulmonary artery (PA) banding that resulted in hypertrophy of the left ventricle (LV) and right ventricle (RV), respectively. We demonstrated that PDE5 expression responded differentially with a decreased expression in the LV and an increased expression in the RV in the Ao-banded model. Similarly, in the PA-banded model, LV showed reduced expression while the RV expression was unaltered. In addition, the expression of cGKI was significantly decreased in the RV of Ao-banded group, correlating inversely with the increase in PDE5 expression.The differential regulation of PDE5 and cGKI expression suggests that the mechanisms involved in hypertrophy could be different in RV vs. LV. Reciprocal PDE5 and cGKI expression in the RV of Ao-banded model suggests functional significance for PDE5 up-regulation

High genetic diversity in a potentially vulnerable tropical tree species despite extreme habitat loss

10.1371/journal.pone.0082632PLoS ONE812-POLN