A decision-making algorithm for remote digital assessments of Alzheimer's Disease.

INTRODUCTION: Remote digital assessments (RDA) such as voice recording, video and motor sensors, olfactory, hearing and vision screenings are now starting to be employed to complement classical biomarker and clinical evidence to identify patients in the early AD stages. Choosing which RDA can be proposed to individual patients is not trivial, and often time consuming. This position paper presents a decision-making algorithm for using RDA during teleconsultations in memory clinic settings. METHOD: The algorithm was developed by an expert panel following the Delphi methodology. RESULTS: The decision-making algorithm is structured as a series of yes-no questions. The resulting questionnaire is freely available online. DISCUSSION: We suggest that the use of screening questionnaires in the context of Memory clinics may help accelerating the adoption of remote digital assessment in everyday clinical practice.

Engagement of Older Adults Receiving Home Care Services and Their Caregivers in Health Decisions in Partnership With Clinical Teams: Protocol for a Multimethod Study to Prioritize and Culturally Adapt Decision Aids for Home Care.

BACKGROUND: Older adults (people aged 65 years and older) face many difficult decisions. Patient decision aids (PtDAs) can help them and their families make informed value-congruent decisions. Some PtDAs have been developed for the home care context, but little is known about scaling them for use with older adults in a different culture. OBJECTIVE: This study aims to (1) assess the scalability of existing PtDAs for older adults in the home care context; (2) prioritize those that best match the decisional needs of older adults in home care; and (3) culturally adapt the prioritized PtDAs so they can be scaled successfully to the Quebec health care system. METHODS: This multimethod study includes 3 phases. All phases will be overseen by a steering committee of older adults, caregivers, health professionals, decision makers, community organization representatives, and researchers with the needed expertise. In phase 1, we will use the Innovation Scalability Self-administered Questionnaire, a validated scalability self-assessment tool, to assess the scalability of 33 PtDAs previously identified in a systematic review. Based on their scalability, their quality (based on the International Patient Decision Aids Standards), and the importance of the decision point, we will retain approximately a third of these. In phase 2, we will conduct a 2-round web-based Delphi to prioritize the PtDAs selected in phase 1. Using a snowball recruitment strategy, we aim to recruit 60 Delphi participants in the province of Quebec, including older adults, caregivers, health professionals, decision makers involved in home care services, and PtDA experts. In the first round, we will ask participants to rate the importance of several PtDA decision points according to various criteria such as prevalence and difficulty on a 5-point Likert scale (1=not important to 5=very important). Approximately 6 of the highest-rated PtDAs will be retained for presentation in the second round, and we will select up to 3 PtDAs judged as having the highest priority for cultural adaptation. In phase 3, using the Chenel framework and user-centered design methods, we will update and adapt the PtDAs to the Quebec health care system and integrate these PtDAs into an interprofessional shared decision-making training program for home care teams. The adapted PtDAs will respect the International Patient Decision Aids Standards criteria. RESULTS: This study was funded in March 2022 by the Canadian Institutes of Health Research. Data collection for the web-based Delphi began in October 2023. Results are expected to be published in May 2024. CONCLUSIONS: This project will provide relevant and culturally appropriate decision support tools for older adults making difficult decisions and their home care teams that will be ready for scaling across the province of Quebec. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/53150.

Using co-creation focus groups to customise a remote multidomain programme designed to increase dementia literacy.

OBJECTIVES: To adapt the content and functionalities of Brain Health PRO, a web-based multidomain program designed to increase dementia literacy, to the context and needs of users, providers and community organisations across Québec, Canada. DESIGN: Five consecutive qualitative co-creation focus group sessions 30-90 min in duration each, exploring potential barriers and facilitators to usability, accessibility, comprehensibility, participant recruitment and retention. SETTING: Virtual meetings. PARTICIPANTS: A 15-member team based in Québec and Ontario, Canada, consisting of 9 researchers (including a graduate student and the project coordinator), representing occupational therapy, sensory rehabilitation, neuropsychology, psychology, health science and research methods, 3 informal caregivers of older adults living with cognitive decline and 3 members of the Federation of Quebec Alzheimer Societies. DATA ANALYSIS: Session recordings were summarised through both qualitative description and thematic analysis. RESULTS: The synthesised recommendations included adjustments around diversity, the complexity and presentation styles of the materials, suggestions on refining the web interface and the measurement approaches; it influenced aspects of participant recruitment, retention efforts and engagement with the content of Brain Health PRO. CONCLUSIONS: Co-creation in dementia prevention research is important because it involves collaboration between researchers, community support and service providers, and persons with lived experience as care providers, in the design and implementation of clinical studies. This approach helps to ensure that the content and presentation of educational material is relevant and meaningful to the target population and those involved in its delivery, and it leads to a greater understanding of their needs and perspectives.

Social Isolation of Older Adults Living in a Neighbourhood of Montreal: A Qualitative Descriptive Study of the Perspectives of Older Adults and Community Stakeholders.

The purpose of this study was to describe the social isolation of older adults in the Côte-des-Neiges neighbourhood (Montreal, Canada) from the perspectives of older adults and community stakeholders. To do so, a descriptive qualitative study was conducted, involving community-dwelling older adults and a variety of key stakeholders from the neighbourhood. Seven focus groups were held, with a total of 37 participants. Focus group transcripts were analyzed using the approach of Miles, Huberman, and Saldaña. Participants reported that social isolation of older adults is characterized by gaps in social interactions (scarcity of social interactions, lack of social support, and unsatisfying relationships) as well as by low social participation that can be depicted in three ways: (1) exclusion by society, (2) self-restriction of participation, and (3) low eagerness to socialize. This study highlights that there is a diversity in how social isolation of older adults manifests itself. It can be the result of a deliberate choice (or not), as well as being desired (or not). These aspects of the phenomenon of social isolation of older adults are still not well described. However, they offer relevant avenues for rethinking approaches to intervention development.

Optimizing Practices, Use, Care, and Services-Antipsychotics (OPUS-AP) in Long-Term Care Centers in Quebec, Canada: A Successful Scale-Up.

OBJECTIVES: To evaluate the scale-up of the OPUS-AP program to improve the care of residents at long-term care (LTC) centers through the systematic implementation of resident-centered approaches to care, the application of nonpharmacologic interventions for the management of behavioral and psychological symptoms of dementia (BPSD), and the deprescribing of antipsychotics where these are not clinically indicated. DESIGN: Prospective, closed cohort. SETTING AND PARTICIPANTS: Residents with major neurocognitive disorder (MNCD) from 24 (phase 1) and 129 (phase 2) publicly funded LTC centers in Quebec, Canada. METHODS: The primary outcome was antipsychotic deprescribing (cessation or dose reduction). Secondary outcomes included changes in benzodiazepine and antidepressant prescriptions, BPSD, and falls. Comparisons were made between assessments at baseline and after 9 months. RESULTS: OPUS-AP phase 2 was conducted from March to December 2019 in 329 clinical wards at 129 LTC centers. At baseline, the 10,601 included residents had a mean age of 82.9: 64.6% were of female sex, 73.7% had a diagnosis of MNCD, and 47.0% had an antipsychotic prescription. These characteristics were similar to those of the 1054 residents at the 24 LTC centers in phase 1. In phase 2, successful antipsychotic deprescribing was achieved for 77.1% of residents in whom this approach was attempted, compared to 85.5% in phase 1. Phase 1 and 2 showed statistically significant improvements in the Cohen-Mansfield Agitation Inventory score and reduced use of benzodiazepines in residents with successful antipsychotic deprescribing. These improvements were of a smaller magnitude in phase 2. Statistically significant reductions in falls were observed in phase 2. CONCLUSIONS AND IMPLICATIONS: The scale-up of the OPUS-AP program from 24 to 129 LTC centers was successful and resulted in a significant reduction in antipsychotic use, as well as improvement in BPSD, and reductions in benzodiazepine use and falls in residents with successful antipsychotic deprescribing.

Implementation conditions leading to the scale-up of an innovation involving the optimal use of antipsychotics in long-term care centers: The Optimizing Practices, Use, Care and Services-Antipsychotics (OPUS-AP) program.

BACKGROUND: Antipsychotics are often used for the first-line management of behavioral and psychological symptoms of dementia despite their limited efficacy and the risk of serious adverse drug events, compounded with disregard for guidelines recommending prioritizing non-pharmacological interventions. Some innovative interventions promote the deprescription of antipsychotics in long term care (LTC) settings. OBJECTIVE: The objective of this article is to present the conditions leading to the scale-up of an innovative program on the appropriate use of antipsychotics in LTC centers. METHODS: The Optimizing Practices, Use, Care and Services-Antipsychotics (OPUS-AP) program is a mixed-method project that aims to improve LTC residents' care through increased knowledge and competency among staff, resident-centered approaches, nonpharmacologic interventions, and by deprescribing antipsychotics when appropriate. This article consists of a qualitative study focused on exploring the implementation conditions of the OPUS-AP program. This study was carried out in an integrated health area of Québec. It consisted of 46 semi-structured interviews with staff members and managers involved in the implementation of OPUS-AP. The qualitative data analysis was inspired by a realistic evaluation approach, which shed light on the causal chain between context, mechanisms, and perceived effects. RESULTS: This study identified certain conditions conducive to scaling up the OPUS-AP program: an integrated, collaborative and evidence-based approach; communications in support of the process; stakeholder engagement at the strategic, tactical and operational levels; an implementation climate conducive to change; and an integrated knowledge translation strategy. CONCLUSION: Despite evidence of clinical efficacy, deprescribing programs require great deal of scaling up efforts. Hence, this study underscores the need to further examine conditions for scaling up medication usage programs in real life contexts.

Quadracyclic adenine: a non-perturbing fluorescent adenine analogue.

Fluorescent-base analogues (FBAs) comprise a group of increasingly important molecules for the investigation of nucleic acid structure and dynamics as well as of interactions between nucleic acids and other molecules. Here, we report on the synthesis, detailed spectroscopic characterisation and base-pairing properties of a new environment-sensitive fluorescent adenine analogue, quadracyclic adenine (qA). After developing an efficient route of synthesis for the phosphoramidite of qA it was incorporated into DNA in high yield by using standard solid-phase synthesis procedures. In DNA qA serves as an adenine analogue that preserves the B-form and, in contrast to most currently available FBAs, maintains or even increases the stability of the duplex. We demonstrate that, unlike fluorescent adenine analogues, such as the most commonly used one, 2-aminopurine, and the recently developed triazole adenine, qA shows highly specific base-pairing with thymine. Moreover, qA has an absorption band outside the absorption of the natural nucleobases (>300 nm) and can thus be selectively excited. Upon excitation the qA monomer displays a fluorescence quantum yield of 6.8 % with an emission maximum at 456 nm. More importantly, upon incorporation into DNA the fluorescence of qA is significantly less quenched than most FBAs. This results in quantum yields that in some sequences reach values that are up to fourfold higher than maximum values reported for 2-aminopurine. To facilitate future utilisation of qA in biochemical and biophysical studies we investigated its fluorescence properties in greater detail and resolved its absorption band outside the DNA absorption region into distinct transition dipole moments. In conclusion, the unique combination of properties of qA make it a promising alternative to current fluorescent adenine analogues for future detailed studies of nucleic acid-containing systems.

8-Modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription.

The occurrence of resistant viruses to any of the anti-HIV-1 compounds used in the current therapies against AIDS underlies the urge for the development of new drug targets and/or new drugs acting through novel mechanisms. While all anti-HIV-1 nucleoside analogues in clinical use and in clinical trials rely on ribose modifications for activity, we designed nucleosides with a natural deoxyribose moiety and modifications of position 8 of the adenine base. Such modifications might induce a steric clash with helix αH in the thumb domain of the p66 subunit of HIV-1 RT at a distance from the catalytic site, causing delayed chain termination. Eleven new 2'-deoxyadenosine analogues modified on position 8 of the purine base were synthesized and tested in vitro and in cell-based assays. In this paper we demonstrate for the first time that chemical modifications on position 8 of 2'-deoxyadenosine induce delayed chain termination in vitro, and also inhibit DNA synthesis when incorporated in a DNA template strand. Furthermore, one of them had moderate anti-HIV-1 activity in cell-culture. Our results constitute a proof of concept indicating that modification on the base moiety of nucleosides can induce delayed polymerization arrest and inhibit HIV-1 replication.

End-capped HyBeacon probes for the analysis of human genetic polymorphisms related to warfarin metabolism.

HyBeacon probes have been used to characterise SNPs in the CYP2C9 and VKORC1 genes associated with variations in the efficiency of warfarin metabolism. PCR amplification of genomic DNA and probe target melting analysis provided a robust and reliable method to differentiate polymorphic sequences at these loci. Probes capped with 5'-trimethoxystilbene were found to exhibit larger fluorescence differences between hybridised and dissociated states than uncapped probes, generating melting peaks of considerably improved height. 3'-Pyrene modifications enhanced probe signal-to-noise and melting peak heights with the additional benefit of acting as PCR stoppers, and 5',3'-doubly capped probes gave the best analytical results.

Potent triple helix stabilization by 5',3'-modified triplex-forming oligonucleotides.

Anthraquinone and pyrene analogues attached to the 3' and/or 5' termini of triplex-forming oligonucleotides (TFOs) by various linkers increased the stability of parallel triple helices. The modifications are simple to synthesize and can be introduced during standard solid-phase oligonucleotide synthesis. Potent triplex stability was achieved by using doubly modified TFOs, which in the most favourable cases gave an increase in melting temperature of 30 degrees C over the unmodified counterparts and maintained their selectivity for the correct target duplex. Such TFOs can produce triplexes with melting temperatures of 40 degrees C at pH 7 even though they do not contain any triplex-stabilizing base analogues. These studies have implications for the design of triplex-forming oligonucleotides for use in biology and nanotechnology.

Time-resolved fluorescent properties of 8-vinyl-deoxyadenosine and 2-amino-deoxyribosylpurine exhibit different sensitivity to their opposite base in duplexes.

8-Vinyl-deoxyadenosine (8VA) has been recently introduced as a fluorescent analogue of adenosine that is less perturbing and less quenched than the well-established 2-amino-deoxyribosylpurine (2AP) probe when inserted in oligonucleotides. To further validate 8VA as a fluorescent substitute of A, we compared the ability of 8VA and 2AP in sequences of the type d(CGT TTT XNX TTT TGC) (with N=8VA or 2AP and X=T and C) to discriminate the nature of the opposite base (Y) in duplexes. For both probes, systematic variations in the amplitudes of the short- and long-lived lifetimes of the fluorescence intensity decays as well as in the amplitude of the fast rotational correlation time of the fluorescence anisotropy decays were observed as a function of the nature of Y. From these parameters, we inferred a stability order 8VA-T > 8VA-G > 8VA-A > 8VA-C, similar to the stability order with the native A base, but different from the stability order with 2AP. Using a combination of molecular mechanics and ab initio calculations, we found that the time-resolved parameters of 8VA, but not the 2AP ones, correlate well with the geometry and the strength of the A-Y base-pairing interaction. This may be rationalized by the smaller structural and electronic perturbations induced by the vinyl group in position 8 as compared to the amino group at position 2. As a consequence, substitution of A by 8VA in a base pair was found to only minimally modify the structure and interaction energy of the base pair. Thus, 8VA can be used as a fluorescent substitute of the natural A, to straightforwardly discriminate the nature of the opposite base. This may find interesting applications notably in the elucidation of the mechanisms and dynamics of the DNA mismatch repair system.

8-vinyl-deoxyadenosine, an alternative fluorescent nucleoside analog to 2'-deoxyribosyl-2-aminopurine with improved properties.

We report here the synthesis and the spectroscopic characterization of 8-vinyl-deoxyadenosine (8vdA), a new fluorescent analog of deoxyadenosine. 8vdA was found to absorb and emit in the same wavelength range as 2'-deoxyribosyl-2-aminopurine (2AP), the most frequently used fluorescent nucleoside analog. Though the quantum yield of 8vdA is similar to that of 2AP, its molar absorption coefficient is about twice, enabling a more sensitive detection. Moreover, the fluorescence of 8vdA was found to be sensitive to temperature and solvent but not to pH (around neutrality) or coupling to phosphate groups. Though 8vdA is base sensitive and susceptible to depurination, the corresponding phosphoramidite was successfully prepared and incorporated in oligonucleotides of the type d(CGT TTT XNX TTT TGC) where N = 8vdA and X = A, T or C. The 8vdA-labeled oligonucleotides gave more stable duplexes than the corresponding 2AP-labeled sequences when X = A or T, indicating that 8vdA is less perturbing than 2AP and probably adopts an anti conformation to preserve the Watson-Crick H-bonding. In addition, the quantum yield of 8vdA is significantly higher than 2AP in all tested oligonucleotides in both their single strand and duplex states. The steady-state and time-resolved fluorescence parameters of 8vdA and 2AP were found to depend similarly on the nature of their flanking residues and on base pairing, suggesting that their photophysics are governed by similar mechanisms. Taken together, our data suggest that 8vdA is a non perturbing nucleoside analog that may be used with improved sensitivity for the same applications as 2AP.