Comparative, cross-sectional study of the format, content and timing of medication safety letters issued in Canada, the USA and the UK

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

Promoters are differentially sensitive to N-terminal mutant huntingtin-mediated transcriptional repression.

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

Measures of Quality of Care for People with HIV: A Scoping Review of Performance Indicators for Primary Care

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

Impact of a chronic disease self-management program on healthcare utilization in eastern Ontario, Canada

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

Overexpression of the components of TFIIF did not recover N-mHtt-mediated transcriptional repression.

<p>ST<i>Hdh</i> Q7/7, Q7/111 and Q111/111 cells were transfected with reporter plasmids driven by the CMV promoter and either an empty expression plasmid or ones driving production of both RAP30 and RAP74 protein. Luciferase activity was normalized to total protein. <i>* P<</i>0.05 relative to ST<i>Hdh</i> Q7/7 cells. <i>∼ P<</i>0.05 relative to vector control within cell type as determined by a two-way ANOVA followed by a Bonferroni post-hoc test. Two-tailed <i>t-</i>tests were performed to determined cell-specific effect of knock-down. Data are shown as mean ± S.E.M. n = 8 for each data set.</p

CMV but not TK promoter activity was decreased in ST<i>Hdh</i> Q7/111 and Q111/111 compared to Q7/7 cells.

<p>Reporter plasmids driven by the CMV (A) and TK (B) promoters were transfected in StHdh Q7/7, Q7/111, and Q111/111 cells. Cell lysates were collected 24 h post-transfection and a DLR™ Assay was performed. <i>* P<</i>0.05 relative to ST<i>Hdh</i> Q7/7 as determined by a one-way ANOVA followed by a Bonferroni post-hoc test. Data are shown as mean ± S.E.M. n = 8 for each data set.</p

TBP overexpression did not recover N-mHtt-mediated transcriptional repression.

<p>ST<i>Hdh</i> Q7/7, Q7/111, and Q111/111 cells were transfected with a CMV reporter plasmid and either an empty expression plasmid, or one driving production of TBP cDNA. Luciferase activity was normalized to total protein. * <i>P<</i>0.05 relative to ST<i>Hdh</i> Q7/7 cells as determined by a two-way ANOVA followed by a Bonferroni post-hoc test. Two-tailed <i>t-</i>tests were performed to determined cell-specific effect of knock-down. Data are shown as mean ± S.E.M. n = 8 per data set.</p

Transcription driven by the−99 CMV promoter was inhibited by N-mHtt.

<p> The −772 CMV promoter was sequentially deleted to 297 (−297 CMV) and 99 (−99 CMV) bp upstream of the transcription start site and promoters were inserted into the pGL3-Basic reporter plasmid. Activity of these plasmids in N548wt and N548hd cells is shown normalized to total protein. * <i>P<</i>0.05 relative to −772 CMV. # <i>P<</i>0.05 relative to −772 CMV and −297 CMV. ∧ <i>P<</i>0.05 relative to −772 CMV, −297 CMV and −99 CMV ∼ <i>P<</i>0.05 relative to N548wt cells as determined by two-way ANOVA followed by a Tamhane’s T2 post-hoc test for unequal variance to analyze effect of promoter deletion, and one-tailed <i>t</i>-test to analyze cell-type effect. Data are shown as mean ± S.E.M. n = 8 per data set.</p

Primers used for linker-scanning mutagenesis.

<p>Primers used for linker-scanning mutagenesis.</p