Helen J Curtis

Mirtrons, an emerging class of atypical miRNA

Post‐transcriptional gene silencing (PTGS) via RNA interference (RNAi) is a vital gene regulatory mechanism for fine‐tuning gene expression. RNAi effectors termed microRNAs (miRNAs) are implicated in various aspects of animal development and normal physiological function, while dysregulation has been linked to several pathologies. Several atypical miRNA biogenesis pathways have been identified, yet in most cases the reasons for their emergence remain unclear. One of these atypical pathways is the mirtron pathway, where short introns are excised by splicing to generate intermediates of the RNAi pathway, with no cleavage by the microprocessor. Closely related pathways involving tailed‐mirtron and simtron biogenesis have also been described. There is extensive evidence that mirtrons function as miRNAs, and while some are evolutionarily conserved across similar species, others appear to have emerged relatively recently. In addition, through exploitation of the potent and sequence‐specific silencing capabilities of RNAi, synthetic mirtrons may have potential for overcoming certain therapeutic challenges. WIREs RNA 2012 doi: 10.1002/wrna.1122

Cross-talking noncoding RNAs contribute to cell-specific neurodegeneration in SCA7.

What causes the tissue-specific pathology of diseases resulting from mutations in housekeeping genes? Specifically, in spinocerebellar ataxia type 7 (SCA7), a neurodegenerative disorder caused by a CAG-repeat expansion in ATXN7 (which encodes an essential component of the mammalian transcription coactivation complex, STAGA), the factors underlying the characteristic progressive cerebellar and retinal degeneration in patients were unknown. We found that STAGA is required for the transcription initiation of miR-124, which in turn mediates the post-transcriptional cross-talk between lnc-SCA7, a conserved long noncoding RNA, and ATXN7 mRNA. In SCA7, mutations in ATXN7 disrupt these regulatory interactions and result in a neuron-specific increase in ATXN7 expression. Strikingly, in mice this increase is most prominent in the SCA7 disease-relevant tissues, namely the retina and cerebellum. Our results illustrate how noncoding RNA–mediated feedback regulation of a ubiquitously expressed housekeeping gene may contribute to specific neurodegeneration.

Different Mechanisms of Recognition and ER Retention by Transmembrane Transcription Factors CREB‐H and ATF6

CREB‐H and activating transcription factor 6 (ATF6) are transmembrane transcription factors that, in response to endoplasmic reticulum (ER) stress, traffic to the Golgi where they are cleaved by specific proteases, producing the N‐terminal domains that effect appropriate transcriptional responses. We show that unlike in ATF6 whose lumenal tail binds BiP and contains determinants for stress sensing and Golgi transport, in CREB‐H the lumenal tail is not involved in ER retention, not required for Golgi transport and does not bind BiP. The main determinant for CREB‐H ER retention resides in a membrane‐proximal cytoplasmic determinant that is conserved in related members of the CREB‐H family, but lacking in ATF6. We refine requirements within the ER‐retention motif (ERM) and show that ERM‐ve variants exhibited constitutive Golgi localization and constitutive cleavage by the Golgi protease, S1P. The ERM also conferred ER retention on a heterologous protein. Furthermore, deletion of the lumenal tail of CREB‐H had no effect on ER retention of parental CREB‐H or Golgi localization of ERM‐ve variants. Importantly, when the lumenal tail of ATF6 was transferred into an ERM‐ve variant, the chimera was now retained in the ER. Together, these data demonstrate novel and qualitatively distinct mechanisms of trafficking and stress signalling in CREB‐H compared to ATF6.

Impact of NICE guidance on tamoxifen prescribing in England 2011–2017: an interrupted time series analysis

BackgroundTamoxifen was recommended by NICE in 2013 for chemoprevention of breast cancer, but a recent survey suggested only a quarter of GPs are aware of this. We set out to measure the uptake of tamoxifen, and the alternative raloxifene, in national prescribing data sets.MethodsTamoxifen and raloxifene data were extracted from England’s monthly prescribing data sets, October 2010–October 2017. We used interrupted time series analysis to reveal national and local responses to guidelines. We investigated variation between practices by calculating percentiles for prescribing rates and ratios of change.ResultsWe found an increase in monthly tamoxifen prescribing following release of the guidelines, with an increase in gradient (p = 0.001) but no step change (p = 0.342). Alongside a small change in raloxifene prescribing we estimate 8450 women took up chemoprevention between 2013 and 2016. We did not find evidence that this was limited to a small group of practices.ConclusionsOur results suggest that the uptake of new guidance on chemoprevention has been slow and has potentially left women exposed to avoidable risk. Improving dissemination of guidance to healthcare professionals and routinely monitoring implementation could help reduce this risk.

Compliance with requirement to report results on the EU Clinical Trials Register: cohort study and web resource

The BMJ Video Playergolb038037 Abstract Objectives To ascertain compliance rates with the European Commission’s requirement that all trials on the EU Clinical Trials Register (EUCTR) post results to the registry within 12 months of completion (final compliance date 21 December 2016); to identify features associated with non-compliance; to rank sponsors by compliance; and to build a tool for live ongoing audit of compliance. Design Retrospective cohort study. Setting EUCTR. Participants 7274 of 11 531 trials listed as completed on EUCTR and where results could be established as due. Main outcome measure Publication of results on EUCTR. Results Of 7274 trials where results were due, 49.5% (95% confidence interval 48.4% to 50.7%) reported results. Trials with a commercial sponsor were substantially more likely to post results than those with a non-commercial sponsor (68.1% v 11.0%, adjusted odds ratio 23.2, 95% confidence interval 19.2 to 28.2); as were trials by a sponsor who conducted a large number of trials (77.9% v 18.4%, adjusted odds ratio 18.4, 15.3 to 22.1). More recent trials were more likely to report results (per year odds ratio 1.05, 95% confidence interval 1.03 to 1.07). Extensive evidence was found of errors, omissions, and contradictory entries in EUCTR data that prevented ascertainment of compliance for some trials. Conclusions Compliance with the European Commission requirement for all trials to post results on to the EUCTR within 12 months of completion has been poor, with half of all trials non-compliant. EU registry data commonly contain inconsistencies that might prevent even regulators assessing compliance. Accessible and timely information on the compliance status of each individual trial and sponsor may help to improve reporting rates.

Trends, geographical variation and factors associated with prescribing of gluten-free foods in English primary care: a cross-sectional study.

Objectives There is substantial disagreement about whether gluten-free foods should be prescribed on the National Health Service. We aim to describe time trends, variation and factors associated with prescribing gluten-free foods in England. Setting English primary care. Participants English general practices. Primary and secondary outcome measures We described long-term national trends in gluten-free prescribing, and practice and Clinical Commissioning Group (CCG) level monthly variation in the rate of gluten-free prescribing (per 1000 patients) over time. We used a mixed-effect Poisson regression model to determine factors associated with gluten-free prescribing rate. Results There were 1.3 million gluten-free prescriptions between July 2016 and June 2017, down from 1.8 million in 2012/2013, with a corresponding cost reduction from £25.4 million to £18.7 million. There was substantial variation in prescribing rates among practices (range 0 to 148 prescriptions per 1000 patients, IQR 7.3–31.8), driven in part by substantial variation at the CCG level, likely due to differences in prescribing policy. Practices in the most deprived quintile of deprivation score had a lower prescribing rate than those in the highest quintile (incidence rate ratio 0.89, 95% CI 0.87 to 0.91). This is potentially a reflection of the lower rate of diagnosed coeliac disease in more deprived populations. Conclusion Gluten-free prescribing is in a state of flux, with substantial clinically unwarranted variation between practices and CCGs.

Is use of homeopathy associated with poor prescribing in English primary care? A cross-sectional study

Objectives Prescribing of homeopathy still occurs in a small minority of English general practices. We hypothesised that practices that prescribe any homeopathic preparations might differ in their prescribing of other drugs. Design Cross-sectional analysis. Setting English primary care. Participants English general practices. Main outcome measures We identified practices that made any homeopathy prescriptions over six months of data. We measured associations with four prescribing and two practice quality indicators using multivariable logistic regression. Results Only 8.5% of practices (644) prescribed homeopathy between December 2016 and May 2017. Practices in the worst-scoring quartile for a composite measure of prescribing quality (>51.4 mean percentile) were 2.1 times more likely to prescribe homeopathy than those in the best category (<40.3) (95% confidence interval: 1.6–2.8). Aggregate savings from the subset of these measures where a cost saving could be calculated were also strongly associated (highest vs. lowest quartile multivariable odds ratio: 2.9, confidence interval: 2.1–4.1). Of practices spending the most on medicines identified as ‘low value’ by NHS England, 12.8% prescribed homeopathy, compared to 3.9% for lowest spenders (multivariable odds ratio: 2.6, confidence interval: 1.9–3.6). Of practices in the worst category for aggregated price-per-unit cost savings, 12.7% prescribed homeopathy, compared to 3.5% in the best category (multivariable odds ratio: 2.7, confidence interval: 1.9–3.9). Practice quality outcomes framework scores and patient recommendation rates were not associated with prescribing homeopathy (odds ratio range: 0.9–1.2). Conclusions Even infrequent homeopathy prescribing is strongly associated with poor performance on a range of prescribing quality measures, but not with overall patient recommendation or quality outcomes framework score. The association is unlikely to be a direct causal relationship, but may reflect underlying practice features, such as the extent of respect for evidence-based practice, or poorer stewardship of the prescribing budget.

Trends and variation in prescribing of low-priority treatments identified by NHS England: a cross-sectional study and interactive data tool in English primary care:

Objectives NHS England recently announced a consultation seeking to discourage the use of treatments it considers to be low-value. We set out to produce an interactive data resource to show savings in each NHS general practice and to assess the current use of these treatments, their change in use over time, and the extent and reasons for variation in such prescribing. Design Cross-sectional analysis. Setting English primary care. Participants English general practices. Main outcome measures We determined the cost per 1000 patients for prescribing of each of 18 treatments identified by NHS England for each month from July 2012 to June 2017, and also aggregated over the most recent year to assess total cost and variation among practices. We used mixed effects linear regression to determine factors associated with cost of prescribing. Results Spend on low-value treatments was £153.5 m in the last year, across 5.8 m prescriptions (mean, £26 per prescription). Among individual treatments, liothyronine had the highest prescribing cost at £29.6 m, followed by trimipramine (£20.2 m). Over time, the overall total number of low-value prescriptions decreased, but the cost increased, although this varied greatly between treatments. Three treatment areas increased in cost and two increased in volume, all others reduced in cost and volume. Annual practice level spending varied widely (median, £2262 per thousand patients; interquartile range £1439 to £3298). Proportion of patients over 65 was strongly associated with low-value prescribing, as was Clinical Commissioning Group. Our interactive data tool was deployed to OpenPrescribing.net where monthly updated figures and graphs can be viewed. Conclusions Prescribing of low-value treatments is extensive but varies widely by treatment, geographic area and individual practice. Despite a fall in prescription numbers, the overall cost of prescribing for low-value items has risen. Prescribing behaviour is clustered by Clinical Commissioning Group, which may represent variation in the optimisation efficiency of medicines, or in some cases access inequality.

Time trends and geographical variation in prescribing of drugs for diabetes in England from 1998 to 2017.

To measure the variation in prescribing of second‐line non‐insulin diabetes drugs.

OpenPrescribing: normalised data and software tool to research trends in English NHS primary care prescribing 1998-2016.

Objectives We aimed to compile and normalise England’s national prescribing data for 1998–2016 to facilitate research on long-term time trends and create an open-data exploration tool for wider use. Design We compiled data from each individual year’s national statistical publications and normalised them by mapping each drug to its current classification within the national formulary where possible. We created a freely accessible, interactive web tool to allow anyone to interact with the processed data. Setting and participants We downloaded all available annual prescription cost analysis datasets, which include cost and quantity for all prescription items dispensed in the community in England. Medical devices and appliances were excluded. Primary and secondary outcome measures We measured the extent of normalisation of data and aimed to produce a functioning accessible analysis tool. Results All data were imported successfully. 87.5% of drugs were matched exactly on name to the current formulary and a further 6.5% to similar drug names. All drugs in core clinical chapters were reconciled to their current location in the data schema, with only 1.26% of drugs not assigned a current chemical code. We created an openly accessible interactive tool to facilitate wider use of these data. Conclusions Publicly available data can be made accessible through interactive online tools to help researchers and policy-makers explore time trends in prescribing.