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1.
Health Expect ; 23(5): 1213-1223, 2020 10.
Article in English | MEDLINE | ID: mdl-32744413

ABSTRACT

OBJECTIVE: While public reporting of hospital-based performance measurement is commonplace, it has lagged in the primary care sector, especially in Canada. Despite the increasing recognition of patients as active partners in the health-care system, little is known about what information about primary care performance is relevant to the Canadian public. We explored patient perspectives and priorities for the public reporting of primary care performance measures. METHODS: We conducted six deliberative dialogue sessions across three Canadian provinces (British Columbia, Ontario, Nova Scotia). Participants were asked to rank and discuss the importance of collecting and reporting on specific dimensions and indicators of primary care performance. We conducted a thematic analysis of the data. RESULTS: Fifty-six patients participated in the dialogue sessions. Measures of access to primary care providers, communication with providers and continuity of information across all providers involved in a patient's care were identified as the highest priority indicators of primary care performance from a patient perspective. Several common measures of quality of care, such as rates of cancer screening, were viewed as too patient dependent to be used to evaluate the health system or primary care provider's performance. CONCLUSIONS: Our findings suggest that public reporting aimed at patient audiences should focus on a nuanced measure of access, incorporation of context reported alongside measurement that is for public audiences, clear reporting on provider communication and a measure of information continuity. Participants highlighted the importance the public places on their providers staying up to date with advances in care.


Subject(s)
Delivery of Health Care , Primary Health Care , British Columbia , Humans , Nova Scotia , Ontario
2.
BMJ Open ; 8(10): e020150, 2018 10 08.
Article in English | MEDLINE | ID: mdl-30297342

ABSTRACT

OBJECTIVES: To assess consistency in the format and content, and overlap of subject and timing, of medication safety letters issued by regulatory health authorities to healthcare providers in Canada, the USA and the UK. DESIGN: A cross-sectional study comparing medication safety letters issued for the purpose of alerting healthcare providers to newly identified medication problems associated with medications already on the market. SETTING: Online databases operated by Health Canada, the US Food and Drug Administration and the UK Medicines and Healthcare products Regulatory Agency were searched to select medication safety letters issued between 1 January 2010 and 31 December 2014. Format, content and timing of each medication safety letter were assessed using an abstraction tool comprising 21 characteristics deemed relevant by consensus of the research team. MAIN OUTCOME MEASURES: Main outcome measures included, first, characteristics (format and content) of medication safety letters and second, overlap of subject and release date across countries. RESULTS: Of 330 medication safety letters identified, 227 dealt with unique issues relating to medications available in all three countries. Of these 227 letters, 21 (9%) medication problems were the subject of letters released in all three countries; 40 (18%) in two countries and 166 (73%) in only one country. Only 13 (62%) of the 21 letters issued in all three countries were released within 6 months of each other. CONCLUSIONS: Significant discrepancies in both the subject and timing of medication safety letters issued by health authorities in three countries (Canada, the USA and the UK) where medical practice is otherwise comparable, raising questions about why, how and when medication problems are identified and communicated to healthcare providers by the authorities. More rapid communication of medication problems and better alignment between authorities could enhance patient safety.


Subject(s)
Correspondence as Topic , Medication Errors/prevention & control , Pharmaceutical Preparations , Canada , Communication , Cross-Sectional Studies , Government Agencies , Humans , Patient Safety , Safety Management , United Kingdom , United States
3.
Can Fam Physician ; 64(1): 17-27, 2018 01.
Article in English | MEDLINE | ID: mdl-29358245

ABSTRACT

OBJECTIVE: To develop an evidence-based guideline to help clinicians make decisions about when and how to safely taper and stop antipsychotics; to focus on the highest level of evidence available and seek input from primary care professionals in the guideline development, review, and endorsement processes. METHODS: The overall team comprised 9 clinicians (1 family physician, 1 family physician specializing in long-term care, 1 geriatric psychiatrist, 2 geriatricians, 4 pharmacists) and a methodologist; members disclosed conflicts of interest. For guideline development, a systematic process was used, including the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Evidence was generated from a Cochrane systematic review of antipsychotic deprescribing trials for the behavioural and psychological symptoms of dementia, and a systematic review was conducted to assess the evidence behind the benefits of using antipsychotics for insomnia. A review of reviews of the harms of continued antipsychotic use was performed, as well as narrative syntheses of patient preferences and resource implications. This evidence and GRADE quality-of-evidence ratings were used to generate recommendations. The team refined guideline content and recommendation wording through consensus and synthesized clinical considerations to address common front-line clinician questions. The draft guideline was distributed to clinicians and stakeholders for review and revisions were made at each stage. RECOMMENDATIONS: We recommend deprescribing antipsychotics for adults with behavioural and psychological symptoms of dementia treated for at least 3 months (symptoms stabilized or no response to an adequate trial) and for adults with primary insomnia treated for any duration or secondary insomnia in which underlying comorbidities are managed. A decision-support algorithm was developed to accompany the guideline. CONCLUSION: Antipsychotics are associated with harms and can be safely tapered. Patients and caregivers might be more amenable to deprescribing if they understand the rationale (potential for harm), are involved in developing the tapering plan, and are offered behavioural advice or management. This guideline provides recommendations for making decisions about when and how to reduce the dose of or stop antipsychotics. Recommendations are meant to assist with, not dictate, decision making in conjunction with patients and families.


Subject(s)
Antipsychotic Agents/standards , Dementia/drug therapy , Deprescriptions , Primary Health Care/standards , Sleep Initiation and Maintenance Disorders/drug therapy , Adult , Aged , Consensus , Dementia/complications , Evidence-Based Medicine/standards , Female , Humans , Male , Middle Aged , Sleep Initiation and Maintenance Disorders/psychology
4.
Can Fam Physician ; 64(1): e1-e12, 2018 01.
Article in French | MEDLINE | ID: mdl-29358261

ABSTRACT

OBJECTIF: Élaborer un guide de pratique clinique fondé sur des données probantes pour aider les cliniciens à prendre des décisions quant au moment et à la façon de réduire et de cesser les antipsychotiques en toute sécurité; insister sur les données les plus probantes et solliciter les contributions des professionnels des soins primaires pour l'élaboration, la révision et l'approbation des lignes directrices. MÉTHODOLOGIE: L'équipe comptait 9 cliniciens (1 médecin de famille, 1 médecin de famille spécialisée en soins de longue durée, 1 psychiatre gériatrique, 2 gériatres, 4 pharmaciens) et une spécialiste en méthodologie; les membres ont divulgué leurs conflits d'intérêts. Un processus systématique a été utilisé pour l'élaboration du guide de pratique, y compris le protocole GRADE (Grading of Recommendations Assessment, Development and Evaluation). Les données probantes ont été tirées d'une revue systématique de Cochrane portant sur des études sur la déprescription des antipsychotiques pour les symptômes comportementaux et psychologiques de la démence. Nous avons effectué une revue systématique pour évaluer les données probantes étayant les bienfaits de l'utilisation des antipsychotiques pour traiter l'insomnie. Nous avons examiné les revues portant sur les torts associés à l'utilisation des antipsychotiques sur une base continue, et nous avons fait une synthèse narrative des préférences des patients et des répercussions sur le plan des ressources. Ces données probantes, de même que l'évaluation de la qualité des données selon GRADE, ont été utilisées pour produire les recommandations. L'équipe a peaufiné le contenu du guide de pratique et le libellé des recommandations, et elle a résumé les considérations d'ordre clinique pour répondre aux questions courantes des cliniciens de première ligne. Une ébauche du guide de pratique a été distribuée à des cliniciens et à des intervenants aux fins d'examen. Des révisions ont été apportées au texte à chaque étape. RECOMMANDATIONS: Nous recommandons la déprescription des antipsychotiques chez les adultes ayant des symptômes comportementaux et psychologiques de démence traités depuis au moins 3 mois (symptômes stabilisés ou sans réponse après un essai adéquat) et chez les adultes souffrant d'insomnie primaire, quelle que soit la durée du traitement, ou d'une insomnie secondaire lorsque les comorbidités sous-jacentes sont prises en charge. Un algorithme décisionnel accompagne le guide de pratique clinique. CONCLUSION: Les antipsychotiques sont associés à des préjudices et il est possible de procéder à un sevrage en toute sécurité. Les patients et leurs aidants peuvent être plus réceptifs à la déprescription s'ils comprennent ce qui la justifie (potentiel de préjudices), s'ils participent à l'élaboration du plan de sevrage et si on leur offre des conseils ou une prise en charge quant aux comportements. Le présent guide de pratique clinique offre des recommandations pour décider du moment et de la façon de réduire la dose d'antipsychotiques ou de les cesser complètement. Les recommandations servent à aider à prendre les décisions conjointement avec les patients et leur famille plutôt qu'à les dicter.

5.
J Am Med Dir Assoc ; 17(7): 673.e1-4, 2016 07 01.
Article in English | MEDLINE | ID: mdl-27289201

ABSTRACT

OBJECTIVES: To assess the effect of a proton pump inhibitor (PPI) deprescribing guideline on PPI usage and PPI drug costs in one long-term care home in Ontario, Canada. DESIGN: Interrupted time-series analysis to compare monthly PPI usage and average monthly PPI cost per resident 9 months before guideline implementation to 12 months after. SETTING: One long-term care home in Ottawa, Ontario, Canada. PARTICIPANTS: Long-term care residents prescribed a PPI over a 21-month period (n = 335). INTERVENTION: PPI deprescribing guideline and decision support tool used during quarterly medication reviews. MEASUREMENTS: (1) Total number of PPI prescriptions (PPI usage) and (2) average PPI drug cost per resident. We also measured the proportion of residents whose PPI was deprescribed in the preguideline period and postguideline period. RESULTS: The deprescribing guideline was associated with a decrease in PPI usage but the association was not statistically significant (-8.7 prescriptions, 95% confidence interval [CI] -22.0 to 4.6). The PPI guideline led to a significant decrease in average monthly PPI drug cost per resident over time (0.16 CAD reduction per month; 95% CI -0.29 to -0.03). In the 9 months before intervention, 57 (27.8%) of 205 eligible residents had their PPI deprescribed, and in the 12 months after intervention 134 (50.0%) of 268 eligible residents had their PPI deprescribed (difference in proportions of 22.2%; 95% CI 13.4-30.4). DISCUSSION/CONCLUSION: The deprescribing guideline was associated with a decline PPI usage; however, this negative association was not statistically significant. PPI usage declined in the initial 6 months after guideline implementation but began to climb back to baseline after this, which may explain the lack of a significant reduction in PPI usage. This suggests that it was difficult to maintain PPI deprescribing efforts long-term. Although implementation of a PPI deprescribing guideline may lead to an initial reduction in PPI usage, and a significant reduction in the average cost of PPI prescriptions over time, it is imperative to explore ways to sustain deprescribing guideline use.


Subject(s)
Drug Costs , Guidelines as Topic , Inappropriate Prescribing/prevention & control , Practice Patterns, Physicians' , Proton Pump Inhibitors/therapeutic use , Female , Homes for the Aged , Humans , Long-Term Care , Male , Ontario , Retrospective Studies
6.
JMIR Res Protoc ; 5(2): e71, 2016 May 18.
Article in English | MEDLINE | ID: mdl-27193076

ABSTRACT

BACKGROUND: Strategies to improve access to health care for people living with human immunodeficiency virus (PLHIV) have demonstrated limited success. Whereas previous approaches have been informed by the views of health providers and decision-makers, it is believed that incorporating patient perspectives into the design and evaluations of health care programs will lead to improved access to health care services. OBJECTIVE: We aim to map the literature on the perspectives of PLHIV concerning access to health care services, to identify gaps in evidence, and to produce an evidence-informed research action plan to guide the Living with HIV program of research. METHODS: This scoping review includes peer-reviewed and grey literature from 1946 to May 2014 using double data extraction. Variations of the search terms "HIV", "patient satisfaction", and "health services accessibility" are used to identify relevant literature. The search strategy is being developed in consultation with content experts, review methodologists, and a librarian, and validated using gold standard studies identified by those stakeholders. The inclusion criteria are (1) the study includes the perspectives of PLHIV, (2) study design includes qualitative, quantitative, or mixed methods, and (3) outcome measures are limited to patient satisfaction, their implied needs, beliefs, and desires in relation to access to health care. The papers are extracted by two independent reviewers, including quality assessment. Data is then collated, summarized, and thematically analyzed. RESULTS: A total of 12,857 references were retrieved, of which 326 documents were identified as eligible in pre-screening, and 64 articles met the inclusion criteria (56% qualitative studies, 38% quantitative studies and 6% mixed-method studies). Only four studies were conducted in Canada. Data synthesis is in progress and full results are expected in June, 2016. CONCLUSIONS: This scoping review will record and characterize the extensive body of literature on perspectives of PLHIV regarding access to health care. A literature repository will be developed to assist stakeholders, decision-makers, and PLHIV in developing and implementing patient-oriented health care programs.

7.
Healthc Policy ; 11(4): 95-110, 2016 05.
Article in English | MEDLINE | ID: mdl-27232240

ABSTRACT

In 2004, Canada's First Ministers committed to reforms that would shape the future of the Canadian healthcare landscape. These agreements included commitments to improved performance reporting within the primary healthcare system. The aim of this paper was to review the state of primary healthcare performance reporting after the public reporting mandate agreed to a decade ago in the Action Plan for Health System Renewal of 2003 expired. A grey literature search was performed to identify reports released by the governmental and independent reporting bodies across Canada. No province, or the federal government, met their performance reporting obligations from the 2004 accords. Although the indicators required to report on in the 2004 Accord no longer reflect the priorities of patients, policy makers and physicians, provinces are also failing to report on these priorities. Canada needs better primary healthcare performance reporting to enable accountability and improvement within and across provinces. Despite the national mandate to improve public health system reporting, an opportunity to learn from the diverse primary healthcare reforms, underway across Canada for the past decade, has already been lost.


Subject(s)
Health Care Reform/organization & administration , Primary Health Care/standards , Canada , Health Care Reform/legislation & jurisprudence , Health Policy , Humans , Primary Health Care/legislation & jurisprudence , Primary Health Care/organization & administration , Quality Assurance, Health Care
8.
Prim Health Care Res Dev ; 17(4): 361-84, 2016 07.
Article in English | MEDLINE | ID: mdl-26627002

ABSTRACT

OBJECTIVES: People with human immunodeficiency virus (HIV) are living longer lives and like many other patients, need a health system better adapted for the management of complex chronic conditions. A key element of system transformation is measuring and reporting on system performance indicators relevant to the different stakeholders. Our objective was to produce a performance measurement framework for assessing the quality of comprehensive community-based primary healthcare for people with HIV. METHODS: Semi-structured interviews were performed with HIV providers, advocates, and policy-makers to obtain input on a draft performance framework, constructed using existing HIV-specific indicators, as well as the use of performance data in improving care for people with HIV. RESULTS: Stakeholders were overwhelmingly supportive of the framework's comprehensiveness. Many noted the absence of indicators addressing social determinants of health and had mixed opinions on the importance of indicators addressing access to after-hours care and the frequency of routine screening for behavioural risk factors. The draft framework was modified to reflect stakeholder input, triangulated against expert opinion and recently released HIV care guidelines, and finalized at 79 indicators. The resources and infrastructure to collect and use performance data will have to be improved for performance measurement to contribute to improving care for people with HIV. CONCLUSIONS: This framework presents a comprehensive though not exhaustive tool to support performance measurement and improvement in the care for people with HIV. However, advances in data collection and use across the system will be needed to support performance measurement driving quality improvement.


Subject(s)
Community Health Services/methods , Community Health Services/standards , HIV Infections/therapy , Primary Health Care/methods , Primary Health Care/standards , Quality Indicators, Health Care/statistics & numerical data , Community Health Services/statistics & numerical data , Humans , Primary Health Care/statistics & numerical data
9.
Can Fam Physician ; 61(9): 780-7, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26623463

ABSTRACT

OBJECTIVE: To identify family medicine residents' barriers to conducting high-quality research for the mandatory family medicine resident scholarly project, as well as to determine possible strategies to encourage research activity among family medicine residents. DESIGN: Descriptive study using an online survey. SETTING: Department of Family Medicine at the University of Ottawa in Ontario. PARTICIPANTS: A total of 54 first- and second-year residents. MAIN OUTCOME MEASURES: Family medicine residents' involvement in research activities, perceived quality of their mandatory scholarly project, intentions for publication and presentation, and attitudes toward potential barriers to and facilitators of conducting high-quality research. RESULTS: Of the 54 residents, 20 (37%) reported that their project was of high quality, 6 (11%) intended to publish their findings, and 2 (4%) intended to present their findings. Respondents indicated that the main barriers to conducting high-quality research were lack of time, interest, and scholarly skills. The proposed solutions to increase participation in scholarly work were to allow full research days to be used in half-day increments and to offer a journal club where residents could learn scholarly activities. CONCLUSION: Family medicine residents found several factors to be considerable barriers to completing the required family medicine resident scholarly project. This indicates that there is a need to change the current approach to developing scholarly skills in family medicine. Greater allotment of and flexibility in protected research time and more sessions focused on developing scholarly skills might facilitate scholarly activity among family medicine residents.


Subject(s)
Biomedical Research , Family Practice/education , Intention , Internship and Residency , Adult , Attitude , Female , Humans , Male , Publishing , Surveys and Questionnaires
10.
BMJ Open ; 5(10): e009715, 2015 Oct 09.
Article in English | MEDLINE | ID: mdl-26453592

ABSTRACT

INTRODUCTION: Potentially inappropriate prescribing (PIP) is frequent and problematic in older patients. Identifying PIP is necessary to improve prescribing quality; ideally, this should be performed at the population level. Screening Tool of Older Persons' potentially inappropriate Prescriptions/Screening Tool to Alert doctors to Right Treatment (STOPP/START) and Beers criteria were developed to identify PIP in clinical settings and are useful at the individual patient level; however, they are time-consuming and costly to apply. Only a subset of these criteria is applicable to routinely collected population-level health administrative data (HAD) because the clinical information necessary to implement these tools is often missing from databases. The performance of subsets of STOPP/START and Beers criteria in HAD compared with clinical data from the same patients is unknown; furthermore, the performance of the updated 2014 STOPP-START and 2012 Beers criteria compared with one another is also unknown. METHODS AND ANALYSIS: A cross-sectional study of linked HAD and clinical data will be conducted to validate the subsets of STOPP/START and Beers criteria applicable to HAD by comparing their performance when applied to clinical and HAD for the same patients. Eligible patients will be 66 years and over and recently admitted to 1 of 6 long-term care facilities in Ottawa, Ontario. The target sample size is 275, but may be less if statistical significance can be achieved sooner. Medication, diagnostic and clinical data will be collected by a consultant pharmacist. The main outcome measure is the proportion of PIP missed by the subset of STOPP/START and Beers criteria applied to HAD when compared with clinical data. ETHICS AND DISSEMINATION: The study was approved by the Ottawa Health Services Network Research Ethics Board, the Bruyère Continuing Care Research Ethics Board and the ethics board of the City of Ottawa Long Term Care Homes. Dissemination will occur via publication, national and international conference presentations, and exchanges with regional, provincial and national stakeholders. TRIAL REGISTRATION NUMBER: NCT02523482.


Subject(s)
Drug-Related Side Effects and Adverse Reactions/epidemiology , Inappropriate Prescribing/statistics & numerical data , Long-Term Care/organization & administration , Potentially Inappropriate Medication List/statistics & numerical data , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , Humans , Male , Ontario/epidemiology , Prevalence , Retrospective Studies
11.
PLoS One ; 10(9): e0136757, 2015.
Article in English | MEDLINE | ID: mdl-26414994

ABSTRACT

The healthcare of people with HIV is transitioning from specialty care to the primary healthcare (PHC) system. However, many of the performance indicators used to measure the quality of HIV care pre-date this transition. The goal of this work was to examine how existing HIV care performance indicators measure the comprehensive and longitudinal care offered in a PHC setting. A scoping review consisting of peer-reviewed and grey literature searches was performed. Two reviewers evaluated study eligibility and indicators in documents meeting inclusion criteria were extracted into a database. Indicators were matched to a PHC performance measurement framework to determine their applicability for evaluating quality of care in the PHC setting. The literature search identified 221 publications, of which 47 met inclusion criteria. 1184 indicators were extracted and removal of duplicates left 558 unique indicators. A majority of the 558 indicators fell under the 'secondary prevention' (12%) and 'care of chronic conditions' (33%) domains when indicators were matched to the PHC performance framework. Despite the imbalance, nearly all performance domains in the PHC framework were populated by at least one indicator with significant concentrations in domains such as patient-provider relationship, patient satisfaction, population and community characteristics, and access to care. Existing performance frameworks for the care of people with HIV provide a comprehensive set of indicators that align well with a PHC performance framework. Nonetheless, some important elements of care, such as patient-reported outcomes, are poorly covered by existing indicators. Advancing our understanding of how the experience of care for people with HIV is impacted by changes in health services delivery, specifically more care within the PHC system, will require performance indicators to capture this aspect of HIV care.


Subject(s)
Delivery of Health Care , HIV Infections/therapy , Primary Health Care , Delivery of Health Care/methods , Delivery of Health Care/standards , Female , Humans , Male , Primary Health Care/methods , Primary Health Care/trends
12.
Stud Health Technol Inform ; 209: 75-83, 2015.
Article in English | MEDLINE | ID: mdl-25980708

ABSTRACT

Access to specialist care is a point of concern for patients, primary care providers, and specialists in Canada. Innovative e-health platforms such as electronic consultation (eConsultation) and referral (eReferral) can improve access to specialist care. These systems allow physicians to communicate asynchronously and could reduce the number of unnecessary referrals that clog wait lists, provide a record of the patient's journey through the referral system, and lead to more efficient visits. Little is known about the current state of eConsultation and eReferral in Canada. The purpose of this work was to identify current systems and gain insight into the design and implementation process of existing systems. An environmental scan approach was used, consisting of a systematic and grey literature review, and targeted semi-structured key informant interviews. Only three eConsultation/eReferral systems are currently in operation in Canada. Four themes emerged from the interviews: eReferral is an end goal for those provinces without an active eReferral system, re-organization of the referral process is a necessity prior to automation, engaging the end-user is essential, and technological incompatibilities are major impediments to progress. Despite the acknowledged need to improve the referral system and increase government spending on health information technology, eConsultation and eReferral systems remain scarce as Canada lags behind the rest of the developed world.


Subject(s)
Health Services Accessibility/organization & administration , Medicine/organization & administration , Models, Organizational , Needs Assessment/organization & administration , Remote Consultation/organization & administration , Canada , Critical Pathways/organization & administration
13.
Prev Med Rep ; 2: 586-90, 2015.
Article in English | MEDLINE | ID: mdl-26844122

ABSTRACT

This study aims to examine patients' patterns of health care utilization before and after participation in a Chronic Disease Self-Management Program (CDSMP). We conducted a pre-post study using health care administrative data from 186 individuals in the Ottawa region who participated in our CDSMP between September 2009 and January 2011. We collected the number of general practitioner/specialist visits, planned/unplanned emergency department visits, and hospitalizations, measured 6 months and 1 year before and after participation in the CDSMP. Multivariate analysis was performed to identify associations between patient characteristics and pre-post CDSMP health care utilization. CDSMP participation showed no effect on number of physician visits, hospitalizations, or emergency department visits. Individuals with > 5 chronic conditions were more likely to visit a physician and the emergency department following the CDSMP than those with 1 chronic condition. Among individuals > 61 years of age, those with the marital status widowed were more likely to visit their physician and the emergency department following the CDSMP than married individuals. To conclude, the CDSMP appeared not to decrease health care utilization. Low baseline utilization rates, short-term follow-ups, and a relatively healthy patient population may have contributed to the program's low impact.

14.
PLoS One ; 7(7): e41152, 2012.
Article in English | MEDLINE | ID: mdl-22815947

ABSTRACT

Huntington's disease (HD) is a neurodegenerative disorder caused by the inheritance of one mutant copy of the huntingtin gene. Mutant huntingtin protein (mHtt) contains an expanded polyglutamine repeat region near the N-terminus. Cleavage of mHtt releases an N-terminal fragment (N-mHtt) which accumulates in the nucleus. Nuclear accumulation of N-mHtt has been directly associated with cellular toxicity. Decreased transcription is among the earliest detected changes that occur in the brains of HD patients, animal and cellular models of HD. Transcriptional dysregulation may trigger many of the perturbations that occur later in disease progression. An understanding of the effects of mHtt may lead to strategies to slow the progression of HD. Current models of N-mHtt-mediated transcriptional dysregulation suggest that abnormal interactions between N-mHtt and transcription factors impair the ability of these transcription factors to associate at N-mHtt-affected promoters and properly regulate gene expression. We tested various aspects of the current models using two N-mHtt-affected promoters in two cell models of HD using overexpression of known N-mHtt-interacting transcription factors, promoter deletion and mutation analyses and in vitro promoter binding assays. Consequently, we proposed a new model of N-mHtt-mediated transcriptional dysregulation centered on the presence of N-mHtt at promoters. In this model, N-mHtt interacts with multiple partners whose presence and affinity for N-mHtt influence the severity of gene dysregulation. We concluded that simultaneous interaction of N-mHtt with multiple binding partners within the transcriptional machinery would explain the gene-specificity of N-mHtt-mediated transcriptional dysregulation, as well as why some genes are affected early in disease progression while others are affected later. Our model explains why alleviating N-mHtt-mediated transcriptional dysregulation through overexpression of N-mHtt-interacting proteins has proven to be difficult and suggests that the most realistic strategy for restoring gene expression across the spectrum of N-mHtt affected genes is by reducing the amount of soluble nuclear N-mHtt.


Subject(s)
Gene Expression Regulation , Mutation , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , Promoter Regions, Genetic , Transcription, Genetic , Animals , Cell Nucleus/metabolism , DNA Primers/genetics , Disease Progression , Humans , Huntingtin Protein , Mutagenesis , Nerve Tissue Proteins/physiology , Nuclear Proteins/physiology , Protein Binding , Protein Structure, Tertiary , Rats , Sequence Analysis, DNA
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