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Host-guest interactions have been increasingly explored for use in the dynamic physical cross-linking of polymeric precursors to form hydrogel networks. However, the orientation of guest motifs is restricted upon macromolecule conjugation. The implications of such restriction on both the kinetics and thermodynamics of the resulting host-guest supramolecular cross-links are poorly understood. Herein, guest cross-linking motifs from controlled regioisomers are demonstrated to yield distinct material properties. Moreover, the underlying phenomena point to a further unexpected impact of modular guest topology on the molecular scale in both the affinity and dynamics of supramolecular complex formation.

Background: The ability to understand and use language is impacted in people with aphasia, often requiring Speech and language therapy interventions to improve their ability to communicate. Currently, there is limited information concerning the experiences of people with aphasia who have undergone speech therapy in many countries such as Ghana where the practice of speech and language therapy is still in its infancy. Such knowledge is known to enhance the uptake of speech and language therapy services and improve both quality and reach., Objective: This study examines the perceived benefits of speech and language therapy interventions for people with aphasia in Ghana from the perspectives of those living with aphasia, their family members and Speech therapists. Additionally, this study sheds light on the interventions employed by Speech therapists in their pursuit of enhancing communicative competence among people with aphasia., Design: We employed a qualitative research design with a purposive sampling technique to recruit seven people with aphasia together with a family member and five Speech therapists., Participants: A total of 19 participants (7 people with aphasia, 7 family members and 5 Speech therapists) were recruited for this study., Methods: A semi-structured interview guide was used. Interviews were audio recorded, transcribed, and subjected to thematic analysis employing the Interpretative Phenomenological Analysis approach, to explore and comprehend the participants' lived experiences ., Results: Our findings revealed that people with aphasia perceived speech and language therapy interventions to be beneficial as it enhanced their communication abilities as well as their quality of life. Family members of people with aphasia valued speech and language interventions as it gave them the opportunity to play a significant role in the recovery process of their family members with aphasia. Speech therapists described using a combination of impairment and functional/communication-based interventions to improve the communication skills and social participation of their clients with aphasia., Conclusions: Findings of the study indicate that people with aphasia and their caregivers experience significantly negative impact on their communication and quality of life, underscoring their profound appreciation for the relief provided by speech and language therapy interventions. Those who have undergone speech and language therapy interventions are inclined to recommend it to others due to its substantial benefits. This can be leveraged to increase the uptake of speech and language therapy and countries where the practise is still in its infancy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Genetic risk scores (GRS) are an emerging and rapidly evolving genomic medicine innovation that may contribute to more precise risk stratification for disease prevention. Inclusion of GRS in routine medical care is imminent, and understanding how physicians perceive and intend to utilize GRS in practice is an important first step in facilitating uptake. This dataset was derived from an electronic survey and comprises one of the first, largest, and broadest samples of United States primary care physician perceptions on the clinical decision-making, benefits, barriers, and utility of GRS to date. The dataset is nearly complete (<1% missing data) and contains responses from 369 PCPs spanning 58 column variables. The public repository includes minimally filtered, de-identified data, all underlying survey versions and items, a data dictionary, and associated analytic files., (© 2023 Published by Elsevier Inc.)

Polygenic risk scores (PRSs) hold promise for disease risk assessment and prevention. The Genomic Medicine at Veterans Affairs (GenoVA) Study is addressing three main challenges to the clinical implementation of PRSs in preventive care: defining and determining their clinical utility, implementing them in time-constrained primary care settings, and countering their potential to exacerbate healthcare disparities. The study processes used to test patients, report their PRS results to them and their primary care providers (PCPs), and promote the use of those results in clinical decision-making are modeled on common practices in primary care. The following diseases were chosen for their prevalence and familiarity to PCPs: coronary artery disease; type 2 diabetes; atrial fibrillation; and breast, colorectal, and prostate cancers. A randomized clinical trial (RCT) design and primary outcome of time-to-new-diagnosis of a target disease bring methodological rigor to the question of the clinical utility of PRS implementation. The study's pragmatic RCT design enhances its relevance to how PRS might reasonably be implemented in primary care. Steps the study has taken to promote health equity include the thoughtful handling of genetic ancestry in PRS construction and reporting and enhanced recruitment strategies to address underrepresentation in research participation. To date, enhanced recruitment efforts have been both necessary and successful: participants of underrepresented race and ethnicity groups have been less likely to enroll in the study than expected but ultimately achieved proportional representation through targeted efforts. The GenoVA Study experience to date offers insights for evaluating the clinical utility of equitable PRS implementation in adult primary care., Competing Interests: Declaration of interests P.N. reports research grants from Allelica, Apple, Amgen, Boston Scientific, Genentech/Roche, and Novartis; and personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Eli Lilly & Co, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, and Novartis; scientific advisory board membership of Esperion Therapeutics, Preciseli, and TenSixteen Bio; status as a scientific co-founder of TenSixteen Bio; equity in MyOme, Preciseli, and TenSixteen Bio; and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. S.A.L. is an employee of Novartis as of July 18, 2022, has previously received sponsored research support from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Fitbit, Medtronic, Premier, and IBM, and has consulted for Bristol Myers Squibb, Pfizer, Blackstone Life Sciences, and Invitae. A.C.F.L. reports owning stock in Fabric Genomics. R.C.G. has received compensation for advising Allelica, Atria, Fabric, Genome Web, Genomic Life, and Juniper Genomics and is co-founder of Genome Medical and Nurture Genomics. The other authors declare no competing interests., (Published by Elsevier Inc.)

Polygenic risk scores (PRS) may improve risk-stratification in preventive care. Their clinical implementation will depend on primary care physicians' (PCPs) uptake. We surveyed PCPs in a national physician database about the perceived clinical utility, benefits, and barriers to the use of PRS in preventive care. Among 367 respondents (participation rate 96.3%), mean (SD) age was 54.9 (12.9) years, 137 (37.3%) were female, and mean (SD) time since medical school graduation was 27.2 (13.3) years. Respondents reported greater perceived utility for more clinical action (e.g., earlier or more intensive screening, preventive medications, or lifestyle modification) for patients with high-risk PRS than for delayed or discontinued prevention actions for low-risk patients (p < 0.001). Respondents most often chose out-of-pocket costs (48%), lack of clinical guidelines (24%), and insurance discrimination concerns (22%) as extreme barriers. Latent class analysis identified 3 subclasses of respondents. Skeptics (n = 83, 22.6%) endorsed less agreement with individual clinical utilities, saw patient anxiety and insurance discrimination as significant barriers, and agreed less often that PRS could help patients make better health decisions. Learners (n = 134, 36.5%) and enthusiasts (n = 150, 40.9%) expressed similar levels of agreement that PRS had utility for preventive actions and that PRS could be useful for patient decision-making. Compared with enthusiasts, however, learners perceived greater barriers to the clinical use of PRS. Overall results suggest that PCPs generally endorse using PRS to guide medical decision-making about preventive care, and barriers identified suggest interventions to address their needs and concerns., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: The use of patient race in medicine is controversial for its potential either to exacerbate or address health disparities. Polygenic risk scores (PRSs) have emerged as a tool for risk stratification models used in preventive medicine. We examined whether PRS results affect primary care physician (PCP) medical decision-making and whether that effect varies by patient race., Methods: Using an online survey with a randomized experimental design among PCPs in a national database, we ascertained decision-making around atherosclerotic cardiovascular disease prevention and prostate cancer screening for case scenario patients who were clinically identical except for randomized reported race., Results: Across 369 PCPs (email open rate = 10.8%, partial completion rate = 93.7%), recommendations varied with PRS results in expected directions (low-risk results, no available PRS results, and high-risk results). Still, physicians randomized to scenarios with Black patients were more likely to recommend statin therapy than those randomized to scenarios with White patients (odds ratio = 1.74, 95% CI = 1.16-2.59, P = .007) despite otherwise identical clinical profiles and independent of PRS results. Similarly, physicians were more likely to recommend prostate cancer screening for Black patients than for White patients (odds ratio = 1.58, 95% CI = 1.06-2.35, P = .025) despite otherwise identical clinical and genetic profiles., Conclusion: Despite advances in precision risk stratification, physicians will likely continue to use patient race implicitly or explicitly in medical decision-making., Competing Interests: Conflict of Interest C.A.B., A.A.A., and J.L.V. are employees of the United States Department of Veterans Affairs. The views expressed in this manuscript do not represent those of the US government or United States Department of Veterans Affairs. All other authors declare no conflicts of interest., (Published by Elsevier Inc.)

Background: Validated computable eligibility criteria use real-world data and facilitate the conduct of clinical trials. The Genomic Medicine at VA (GenoVA) Study is a pragmatic trial of polygenic risk score testing enrolling patients without known diagnoses of 6 common diseases: atrial fibrillation, coronary artery disease, type 2 diabetes, breast cancer, colorectal cancer, and prostate cancer. We describe the validation of computable disease classifiers as eligibility criteria and their performance in the first 16 months of trial enrollment., Methods: We identified well-performing published computable classifiers for the 6 target diseases and validated these in the target population using blinded physician review. If needed, classifiers were refined and then underwent a subsequent round of blinded review until true positive and true negative rates ≥80% were achieved. The optimized classifiers were then implemented as pre-screening exclusion criteria; telephone screens enabled an assessment of their real-world negative predictive value (NPV-RW)., Results: Published classifiers for type 2 diabetes and breast and prostate cancer achieved desired performance in blinded chart review without modification; the classifier for atrial fibrillation required two rounds of refinement before achieving desired performance. Among the 1077 potential participants screened in the first 16 months of enrollment, NPV-RW of the classifiers ranged from 98.4% for coronary artery disease to 99.9% for colorectal cancer. Performance did not differ by gender or race/ethnicity., Conclusions: Computable disease classifiers can serve as efficient and accurate pre-screening classifiers for clinical trials, although performance will depend on the trial objectives and diseases under study., Competing Interests: Declaration of Competing Interest The authors declare they have no competing interests., (Published by Elsevier Inc.)

Implementation of polygenic risk scores (PRS) may improve disease prevention and management but poses several challenges: the construction of clinically valid assays, interpretation for individual patients, and the development of clinical workflows and resources to support their use in patient care. For the ongoing Veterans Affairs Genomic Medicine at Veterans Affairs (GenoVA) Study we developed a clinical genotype array-based assay for six published PRS. We used data from 36,423 Mass General Brigham Biobank participants and adjustment for population structure to replicate known PRS-disease associations and published PRS thresholds for a disease odds ratio (OR) of 2 (ranging from 1.75 (95% CI: 1.57-1.95) for type 2 diabetes to 2.38 (95% CI: 2.07-2.73) for breast cancer). After confirming the high performance and robustness of the pipeline for use as a clinical assay for individual patients, we analyzed the first 227 prospective samples from the GenoVA Study and found that the frequency of PRS corresponding to published OR > 2 ranged from 13/227 (5.7%) for colorectal cancer to 23/150 (15.3%) for prostate cancer. In addition to the PRS laboratory report, we developed physician- and patient-oriented informational materials to support decision-making about PRS results. Our work illustrates the generalizable development of a clinical PRS assay for multiple conditions and the technical, reporting and clinical workflow challenges for implementing PRS information in the clinic., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

There is a well-validated association between SLCO1B1 (rs4149056) and statin-associated muscle symptoms (SAMS). Preemptive SLCO1B1 pharmacogenetic (PGx) testing may diminish the incidence of SAMS by identifying individuals with increased genetic risk before statin initiation. Despite its potential clinical application, the cost implications of SLCO1B1 testing are largely unknown. We conducted a cost-consequence analysis of preemptive SLCO1B1 testing (PGx+) versus usual care (PGx-) among Veteran patients enrolled in the Integrating Pharmacogenetics in Clinical Care (I-PICC) Study. The assessment was conducted using a health system perspective and 12-month time horizon. Incremental costs of SLCO1B1 testing and downstream medical care were estimated using data from the U.S. Department of Veterans Affairs' Managerial Cost Accounting System. A decision analytic model was also developed to model 1-month cost and SAMS-related outcomes in a hypothetical cohort of 10,000 Veteran patients, where all patients were initiated on simvastatin. Over 12 months, 13.5% of PGx+ (26/193) and 11.2% of PGx- (24/215) participants in the I-PICC Study were prescribed Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline-concordant statins (Δ2.9%, 95% CI -4.0% to 10.0%). Differences in mean per-patient costs for lipid therapy prescriptions, including statins, for PGx+ compared to PGx- participants were not statistically significant (Δ USD 9.53, 95% CI -0.86 to 22.80 USD). Differences in per-patient costs attributable to the intervention, including PGx testing, lipid-lowering prescriptions, SAMS, laboratory and imaging expenses, and primary care and cardiology services, were also non-significant (Δ- USD 1004, 95% CI -2684 to 1009 USD). In the hypothetical cohort, SLCO1B1 -informed statin therapy averted 109 myalgias and 3 myopathies at 1-month follow up. Fewer statin discontinuations (78 vs. 109) were also observed, but the SLCO1B1 testing strategy was 96 USD more costly per patient compared to no testing (124 vs. 28 USD). The implementation of SLCO1B1 testing resulted in small, non-significant increases in the proportion of patients receiving CPIC-concordant statin prescriptions within a real-world primary care context, diminished the incidence of SAMS, and reduced statin discontinuations in a hypothetical cohort of 10,000 patients. Despite these effects, SLCO1B1 testing administered as a standalone test did not result in lower per-patient health care costs at 1 month or over 1 year of treatment. The inclusion of SLCO1B1 , among other well-validated pharmacogenes, into preemptive panel-based testing strategies may provide a better balance of clinical benefit and cost.