IMPACT OF HEALTH TECHNOLOGY ASSESSMENT REPORTS ON HOSPITAL DECISION MAKERS - 10-YEAR INSIGHT FROM A HOSPITAL UNIT IN SHERBROOKE, CANADA: IMPACT OF HEALTH TECHNOLOGY ASSESSMENT ON HOSPITAL DECISIONS.

OBJECTIVES: The overarching goal of this research was to (i) evaluate the impact of reports with recommendations provided by a hospital-based health technology assessment (HB-HTA) unit on the local hospital decision-making processes and implementation activities and (ii) identify the underlying factors of the nonimplementation of recommendations. METHODS: All reports produced by the HB-HTA unit between December 2003 and March 2013 were retrieved, and hospital decision makers who requested these reports were solicited for enrolment. Participants were interviewed using a mixed design survey. RESULTS: Twenty reports, associated with fifteen decision makers, fulfilled the study criteria. Nine decision makers accepted to participate, corresponding to thirteen reports and twenty-three recommendations. Of the twenty-three recommendations issued, 65 percent were implemented, 9 percent were accepted for implementation but not implemented, and 26 percent were declined. In terms of the utility of each report to guide decision makers, 92 percent of the reports were considered in the decision-making process; 85 percent had one or more recommendations adopted; and 77 percent had recommendations implemented. The most frequently mentioned reasons for nonimplementation were related to contextual factors (64 percent), production/diffusion process factors (14 percent), content/format factors (14 percent), or other factors (9 percent). Among the contextual factors, the complexity of the changes (i.e., administrative reasons), budget and resources constraints, failure to identify administrative responsibility to carry out the recommendation, and nonpriority status of the HTA recommendation, were provided. CONCLUSIONS: This study highlights that although HB-HTA reports are useful to hospital managers in their decision-making processes, certain barriers such as contextual factors need to be better addressed to improve HB-HTA efficiency and usefulness.

Speech Recognition for Medical Dictation: Overview in Quebec and Systematic Review.

Speech recognition is increasingly used in medical reporting. The aim of this article is to identify in the literature the strengths and weaknesses of this technology, as well as barriers to and facilitators of its implementation. A systematic review of systematic reviews was performed using PubMed, Scopus, the Cochrane Library and the Center for Reviews and Dissemination through August 2017. The gray literature has also been consulted. The quality of systematic reviews has been assessed with the AMSTAR checklist. The main inclusion criterion was use of speech recognition for medical reporting (front-end or back-end). A survey has also been conducted in Quebec, Canada, to identify the dissemination of this technology in this province, as well as the factors leading to the success or failure of its implementation. Five systematic reviews were identified. These reviews indicated a high level of heterogeneity across studies. The quality of the studies reported was generally poor. Speech recognition is not as accurate as human transcription, but it can dramatically reduce turnaround times for reporting. In front-end use, medical doctors need to spend more time on dictation and correction than required with human transcription. With speech recognition, major errors occur up to three times more frequently. In back-end use, a potential increase in productivity of transcriptionists was noted. In conclusion, speech recognition offers several advantages for medical reporting. However, these advantages are countered by an increased burden on medical doctors and by risks of additional errors in medical reports. It is also hard to identify for which medical specialties and which clinical activities the use of speech recognition will be the most beneficial.

Is radiofrequency ablation of varicose veins a valuable option? A systematic review of the literature with a cost analysis.

BACKGROUND: Since the 1990s, new techniques for the treatment of varicose veins have emerged, including radiofrequency ablation (RFA) and laser treatment. We performed a study to compare the safety, efficacy and outcomes of RFA compared to those of open surgery and laser ablation for the treatment of varicose veins. We also carried out a cost analysis of RFA compared to open surgery to assess whether RFA could help free up operating room time by being performed in an outpatient context. METHODS: We conducted a systematic literature review (publication date May 2010-September 2013 for articles in English, January 1991-September 2013 for those in French). We used several checklists to measure the quality of the studies. We also collected data on costing. RESULTS: The literature search identified 924 publications, of which 38 were retained for analysis: 15 literature reviews, 1 good-practice guideline and 22 new primary studies. The overall level of evidence was low to moderate owing to the limited sample sizes, lack of information on patient characteristics and lack of standardization of the outcome measures. However, the results obtained are consistent from study to study. In the short and medium term, RFA is considered as effective as open surgery or laser treatment (moderate level of evidence) and presents fewer major and minor complications than open surgery (low level of evidence). Radiofrequency ablation can be performed on an outpatient basis. We calculated that RFA would be about $110-$220 more expensive per patient than open surgery. CONCLUSION: Radiofrequency ablation is a valuable alternative to open surgery and would free up operating room time in a context of low accessibility.

CONTEXTE: Depuis les années 1990, de nouvelles techniques pour le traitement des varices ont émergé, y compris l'ablation par radiofréquence (ARF) et le traitement au laser. Nous avons procédé à une étude afin de comparer l'innocuité, l'efficacité et les résultats de l'ARF à ceux de la chirurgie ouverte et de l'ablation par laser pour le traitement des varices. Nous avons aussi procédé à une analyse des coûts de l'ARF comparativement à la chirurgie pour vérifier si, en étant effectuée en consultation externe, l'ARF permet de libérer du temps de bloc opératoire. MÉTHODES: Nous avons réalisé une revue systématique de la documentation (articles publiés entre mai 2010 et septembre 2013 en langue anglaise, et entre janvier 1991 et septembre 2013 en langue française). Nous avons utilisé plusieurs séries de critères pour mesurer la qualité des études. Nous avons aussi recueilli des données sur l'estimation des coûts. RÉSULTATS: La recherche documentaire a permis de recenser 924 publications, dont 38 ont été retenues pour analyse : 15 examens documentaires, 1 directive de pratique optimale et 22 études principales. Le niveau de preuve global a été jugé de faible à modéré en raison de la taille limitée des échantillons, du manque d'information sur les caractéristiques des patients et de l'absence de normalisation des mesures paramétriques. Toutefois, les résultats obtenus concordent d'une étude à l'autre. À court et à moyen terme, l'ARF est considérée aussi efficace que la chirurgie ouverte ou que le traitement au laser (niveau de preuve modéré) et s'accompagne de moins de complications majeures et mineures que la chirurgie ouverte (faible niveau de preuve). L'ablation par radiofréquence peut être effectuée en consultation externe. Nous avons calculé que l'ARF couterait environ 110 à 220 $ de plus par patient comparativement à la chirurgie. CONCLUSION: L'ablation par radiofréquence est une solution de rechange valable à la chirurgie ouverte et pourrait libérer du temps de bloc opératoire dans un contexte d'accès restreint.

Pressure Infusion Cuff and Blood Warmer during Massive Transfusion: An Experimental Study About Hemolysis and Hypothermia.

BACKGROUND: Blood warmers were developed to reduce the risk of hypothermia associated with the infusion of cold blood products. During massive transfusion, these devices are used with compression sleeve, which induce a major stress to red blood cells. In this setting, the combination of blood warmer and compression sleeve could generate hemolysis and harm the patient. We conducted this study to compare the impact of different pressure rates on the hemolysis of packed red blood cells and on the outlet temperature when a blood warmer set at 41.5°C is used. METHODS: Pressure rates tested were 150 and 300 mmHg. Ten packed red blood cells units were provided by Héma-Québec and each unit was sequentially tested. RESULTS: We found no increase in hemolysis either at 150 or 300 mmHg. By cons, we found that the blood warmer was not effective at warming the red blood cells at the specified temperature. At 150 mmHg, the outlet temperature reached 37.1°C and at 300 mmHg, the temperature was 33.7°C. CONCLUSION: To use a blood warmer set at 41.5°C in conjunction with a compression sleeve at 150 or 300 mmHg does not generate hemolysis. At 300 mmHg a blood warmer set at 41.5°C does not totally avoid a risk of hypothermia.

Are drug-coated balloons cost effective for femoropopliteal occlusive disease? A comparison of bare metal stents and uncoated balloons.

AIM: To perform a cost-effectiveness analysis to help hospital decision-makers with regard to the use of drug-coated balloons compared with bare metal stents and uncoated balloons for femoropopliteal occlusive disease. METHODS: Clinical outcomes were extracted from the results of meta-analyses already published, and cost units are those used in the Quebec healthcare network. The literature review was limited to the last four years to obtain the most recent data. The cost-effectiveness analysis was based on a 2-year perspective, and risk factors of reintervention were considered. RESULTS: The cost-effectiveness analysis indicated that drug-coated balloons were generally more efficient than bare metal stents, particularly for patients with higher risk of reintervention (up to CAD$1686 per patient TASC II C or D). Compared with uncoated balloons, results indicated that drug-coated balloons were more efficient if the reintervention rate associated with uncoated balloons is very high and for patients with higher risk of reintervention (up to CAD$3301 per patient). CONCLUSION: The higher a patient's risk of reintervention, the higher the savings associated with the use of a drug-coated balloon will be. For patients at lower risk, the uncoated balloon strategy is still recommended as a first choice for endovascular intervention.

A G-rich element forms a G-quadruplex and regulates BACE1 mRNA alternative splicing.

ß-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the transmembrane aspartyl protease that catalyzes the first cleavage step in the proteolysis of the APP to the amyloid ß-protein (Aß), a process involved in the pathogenesis of Alzheimer disease. BACE1 pre-mRNA undergoes complex alternative splicing, the regulation of which is not well understood. We identified a G-rich sequence within exon 3 of BACE1 involved in controlling splice site selection. Mutation of the G-rich sequence decreased use of the normal 5' splice site of exon 3, which leads to full-length and proteolytically active BACE1, and increased use of an alternative splice site, which leads to a shorter, essentially inactive isoform. Nuclease protection assays, nuclear magnetic resonance, and circular dichroism spectroscopy revealed that this sequence folds into a G-quadruplex structure. Several proteins were identified as capable of binding to the G-rich sequence, and one of these, heterogeneous nuclear ribonucleoprotein H, was found to regulate BACE1 exon 3 alternative splicing and in a manner dependent on the G-rich sequence. Knockdown of heterogeneous nuclear ribonucleoprotein H led to a decrease in the full-length BACE1 mRNA isoform as well as a decrease in Aß production from APP, suggesting new possibilities for therapeutic approaches to Alzheimer's disease.

Structural basis of G-tract recognition and encaging by hnRNP F quasi-RRMs.

The heterogeneous nuclear ribonucleoprotein (hnRNP) F is involved in the regulation of mRNA metabolism by specifically recognizing G-tract RNA sequences. We have determined the solution structures of the three quasi-RNA-recognition motifs (qRRMs) of hnRNP F in complex with G-tract RNA. These structures show that qRRMs bind RNA in a very unusual manner, with the G-tract 'encaged', making the qRRM a novel RNA binding domain. We defined a consensus signature sequence for qRRMs and identified other human qRRM-containing proteins that also specifically recognize G-tract RNAs. Our structures explain how qRRMs can sequester G-tracts, maintaining them in a single-stranded conformation. We also show that isolated qRRMs of hnRNP F are sufficient to regulate the alternative splicing of the Bcl-x pre-mRNA, suggesting that hnRNP F would act by remodeling RNA secondary and tertiary structures.

hnRNP A1 and hnRNP H can collaborate to modulate 5' splice site selection.

The mammalian proteins hnRNP A1 and hnRNP H control many splicing decisions in viral and cellular primary transcripts. To explain some of these activities, we have proposed that self-interactions between bound proteins create an RNA loop that represses internal splice sites while simultaneously activating the external sites that are brought in closer proximity. Here we show that a variety of hnRNP H binding sites can affect 5' splice site selection. The addition of two sets of hnRNP H sites in a model pre-mRNA modulates 5' splice site selection cooperatively, consistent with the looping model. Notably, binding sites for hnRNP A1 and H on the same pre-mRNA can similarly collaborate to modulate 5' splice site selection. The C-terminal portion of hnRNP H that contains the glycine-rich domains (GRD) is essential for splicing activity, and it can be functionally replaced by the GRD of hnRNP A1. Finally, we used the bioluminescence resonance energy transfer (BRET) technology to document the existence of homotypic and heterotypic interactions between hnRNP H and hnRNP A1 in live cells. Overall, our study suggests that interactions between different hnRNP proteins bound to distinct locations on a pre-mRNA can change its conformation to affect splicing decisions.

[Guiding and integrating to control and diversify splicing]. / Guider et intégrer pour un épissage diversifié

Recent studies directed at understanding alternative splicing control have produced an expanding list of regulators that can enhance or silence the use of splice sites by binding to specific sequences. A fine balance in the expression and the combinatorial use of these factors would help to adapt splicing decisions to a variety of situations. Additional levels of control are provided by tightly connecting the activity of alternative splicing factors with other cellular processes such as signal transduction and transcription. Combining classical experiments and high-throughput approaches is now confirming the important contribution of alternative splicing to proteomic diversity while helping to decipher the underlying networks of splicing regulation.

hnRNP proteins and splicing control.

Proteins of the heterogeneous nuclear ribonucleoparticles (hnRNP) family form a structurally diverse group of RNA binding proteins implicated in various functions in metazoans. Here we discuss recent advances supporting a role for these proteins in precursor-messenger RNA (pre-mRNA) splicing. Heterogeneous nuclear RNP proteins can repress splicing by directly antagonizing the recognition of splice sites, or can interfere with the binding of proteins bound to enhancers. Recently, hnRNP proteins have been shown to hinder communication between factors bound to different splice sites. Conversely, several reports have described a positive role for some hnRNP proteins in pre-mRNA splicing. Moreover, cooperative interactions between bound hnRNP proteins may encourage splicing between specific pairs of splice sites while simultaneously hampering other combinations. Thus, hnRNP proteins utilize a variety of strategies to control splice site selection in a manner that is important for both alternative and constitutive pre-mRNA splicing.

Intronic binding sites for hnRNP A/B and hnRNP F/H proteins stimulate pre-mRNA splicing.

hnRNP A/B proteins modulate the alternative splicing of several mammalian and viral pre-mRNAs, and are typically viewed as proteins that enforce the activity of splicing silencers. Here we show that intronic hnRNP A/B-binding sites (ABS) can stimulate the in vitro splicing of pre-mRNAs containing artificially enlarged introns. Stimulation of in vitro splicing could also be obtained by providing intronic ABS in trans through the use of antisense oligonucleotides containing a non-hybridizing ABS-carrying tail. ABS-tailed oligonucleotides also improved the in vivo inclusion of an alternative exon flanked by an enlarged intron. Notably, binding sites for hnRNP F/H proteins (FBS) replicate the activity of ABS by improving the splicing of an enlarged intron and by modulating 5' splice-site selection. One hypothesis formulated to explain these effects is that bound hnRNP proteins self-interact to bring in closer proximity the external pair of splice sites. Consistent with this model, positioning FBS or ABS at both ends of an intron was required to stimulate splicing of some pre-mRNAs. In addition, a computational analysis of the configuration of putative FBS and ABS located at the ends of introns supports the view that these motifs have evolved to support cooperative interactions. Our results document a positive role for the hnRNP A/B and hnRNP F/H proteins in generic splicing, and suggest that these proteins may modulate the conformation of mammalian pre-mRNAs.

Heterogeneous nuclear ribonucleoprotein F/H proteins modulate the alternative splicing of the apoptotic mediator Bcl-x.

Bcl-x is a member of the Bcl-2 family of proteins that are key regulators of apoptosis. The Bcl-x pre-mRNA is alternatively spliced to yield Bcl-x(S) and Bcl-x(L), two isoforms that have been associated, respectively, with the promotion and the prevention of apoptosis. We have investigated some of the elements and factors involved in the production of these two splice variants. Deletion mutagenesis using a human Bcl-x minigene identifies two regions in exon 2 that modulate Bcl-x 5'-splice site selection in human HeLa cells. One region (B3) is located upstream of the Bcl-x(L) 5'-splice site and enforces Bcl-x(L) production in cells and splicing extracts. The other region (B2) is located immediately downstream of the 5'-splice site of Bcl-x(S) and favors Bcl-x(S) production in vivo and in vitro. A 30-nucleotide G-rich element (B2G) is responsible for the activity of the B2 element. We show that recombinant heterogeneous nuclear ribonucleoprotein (hnRNP) F and H proteins bind to B2G, and mutating the G stretches abolishes binding. Moreover, the addition of hnRNP F to a HeLa extract improved the production of the Bcl-x(S) variant in a manner that was dependent on the integrity of the G stretches in B2G. Consistent with the in vitro results, small interfering RNA-mediated RNA interference targeting hnRNP F and H decreased the Bcl-x(S)/Bcl-x(L) ratio of plasmid-derived and endogenously produced Bcl-x transcripts. Our results document a positive role for the hnRNP F/H proteins in the production of the proapoptotic regulator Bcl-x(S.).