Free-of-charge medicine schemes in the NHS: A local and regional drug and therapeutic committee's experience

INTRODUCTION: Free-of-charge (FoC) medicine schemes are increasingly available and allow access to investigational treatments outside clinical trials or in advance of licensing or NHS commissioning. METHODS: We retrospectively reviewed FoC medicine schemes evaluated between 2013 and 2019 by a single NHS trust and a regional drug and therapeutics committee (DTC). The details of each locally reviewed FoC scheme, and any nationally available Medicines and Healthcare products Regulatory Agency Early Access to Medicines Scheme (MHRA EAMS) in the same period, were recorded and categorised. RESULTS: Most FoC schemes (95%) allowed access to medicines intended to address an unmet clinical need. Over 7 years, 90% were company-FoC schemes and 10% were MHRA EAMS that were locally reviewed. Phase 3 clinical trial data were available for 44% of FoC schemes, 37% had phase 2 data and 19% were supported only by phase 1 data, retrospective observational studies or preclinical data. Utilisation of company-FoC schemes increased on average by 50% per year, while MHRA EAMS schemes showed little growth. CONCLUSION: Company-FoC medicine schemes are increasingly common. This may indicate a preference for pharmaceutical companies to independently co-ordinate schemes. Motivations for company-FoC schemes remain unclear and many provide access to treatments that are yet to be evaluated in appropriately conducted clinical trials, and whose efficacy and risk of harm remain uncertain. There is no standardisation of this practice and there is no regulatory oversight. Moreover, no standardised data collection framework is in place that could demonstrate the utility of such programmes in addressing unmet clinical need or to allow generation of further evidence

The Cam-type Deformity of the Proximal Femur Arises in Childhood in Response to Vigorous Sporting Activity

Background: The prevalence of a cam-type deformity in athletes and its association with vigorous sports activities during and after the growth period is unknown. Questions/purposes: We therefore compared the prevalence and occurrence of a cam-type deformity by MRI in athletes during childhood and adolescence with an age-matched control group. Patients and Methods: We retrospectively reviewed 72 hips in 37 male basketball players with a mean age of 17.6years (range, 9-25years) and 76 asymptomatic hips of 38 age-matched volunteers who had not participated in sporting activities at a high level. Results: Eleven (15%) of the 72 hips in the athletes were painful and had positive anterior impingement tests on physical examination. Internal rotation of the hip averaged 30.1° (range, 15°-45°) in the control group compared with only 18.9° (range, 0°-45°) in the athletes. The maximum value of the alpha angle throughout the anterosuperior head segment was larger in the athletes (average, 60.5°±9°), compared with the control group (47.4°±4°). These differences became more pronounced after closure of the capital growth plate. Overall, the athletes had a 10-fold increased likelihood of having an alpha angle greater than 55° at least at one measurement position. Conclusions: Our observations suggest a high intensity of sports activity during adolescence is associated with a substantial increase in the risk of cam-type impingement. These patients also may be at increased risk of subsequent development of secondary coxarthrosis. Level of Evidence: Level II, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidenc

Evaluation of quality of life in adults with neurofibromatosis 1 (NF1) using the Impact of NF1 on Quality Of Life (INF1-QOL) questionnaire

Background Neurofibromatosis 1 (NF1) is an inherited, multi-system, tumour suppressor disorder with variable complications that cause psychological distress and social isolation. The study aim was to develop and validate a disease-specific questionnaire to measure quality of life (QOL) in NF1 that is suitable both as an assessment tool in clinical practice and in clinical trials of novel therapy. Methods The Impact of NF1 on Quality of Life (INF1-QOL) questionnaire was developed by a literature search for common terms, focus group (n=6), semi-structured interviews (n=21), initial drafts (n =50) and final 14 item questionnaire (n=50). Bivariate correlations between items, exploratory factor analysis, correlations with severity and EuroQol were employed. Results INF1-QOL showed good internal reliability (Cronbach’s alpha 0.87), mean total INF1-QOL score was 8.64 (SD 6.3), median 7.00, range 0-30 (possible range 0-42); no significant correlations with age or gender. The mean total EuroQol score was 7.38 (SD 2.87), median 6.5, mean global EuroQol score was 76.34 (SD 16.56), median 80. Total INF1-QOL score correlated with total EuroQol r=0.82, p<0.0001. The highest impact on QOL was moderate or severe problems with anxiety and depression (32%) and negative effects of NF1 on role and outlook on life (42%). The mean inter-relater reliability for grading of clinical severity scores was 0.71 (range 0.65-0.79), and intra-class correlation was 0.92. The mean clinical severity score was 1.95 (SD 0.65) correlating r=0.34 with total INF1-QOL score p<0.05 and correlated 0.37 with total EuroQol score p<0.01. The clinical severity score was mild in 17 (34%), moderate in 16 (32%) and 17 (34%) individuals had severe disease. Conclusions INF1-QOL is a validated, reliable disease specific questionnaire that is easy and quick to complete. Role and outlook on life and anxiety and depression have the highest impact on QOL indicating the variability, severity and unpredictability of NF1. INFI-QOL correlates moderately with clinical severity. The moderate relationship between INF1-QOL and physician rated severity emphasizes the difference between clinical and patient perception. INFI-QOL will be useful in individual patient assessment and as an outcome measure for clinical trials

Structural and mechanistic characterization of 6S RNA from the hyperthermophilic bacterium Aquifex aeolicus

© 2015 Elsevier B.V. and Socie;acuteacute& Franc de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved. Bacterial 6S RNAs competitively inhibit binding of RNA polymerase (RNAP) holoenzymes to DNA promoters, thereby globally regulating transcription. RNAP uses 6S RNA itself as a template to synthesize short transcripts, termed pRNAs (product RNAs). Longer pRNAs (approx. ≥ 10 nt) rearrange the 6S RNA structure and thereby disrupt the 6S RNA:RNAP complex, which enables the enzyme to resume transcription at DNA promoters. We studied 6S RNA of the hyperthermophilic bacterium Aquifex aeolicus, representing the thermodynamically most stable 6S RNA known so far. Applying structure probing and NMR, we show that the RNA adopts the canonical rod-shaped 6S RNA architecture with little structure formation in the central bulge (CB) even at moderate temperatures (≤37°C). 6S RNA:pRNA complex formation triggers an internal structure rearrangement of 6S RNA, i.e. formation of a so-called central bulge collapse (CBC) helix. The persistence of several characteristic NMR imino proton resonances upon pRNA annealing demonstrates that defined helical segments on both sides of the CB are retained in the pRNA-bound state, thus representing a basic framework of the RNA's architecture. RNA-seq analyses revealed pRNA synthesis from 6S RNA in A. aeolicus, identifying 9 to ∼17-mers as the major length species. A. aeolicus 6S RNA can also serve as a template for in vitro pRNA synthesis by RNAP from the mesophile Bacillus subtilis. Binding of a synthetic pRNA to A. aeolicus 6S RNA blocks formation of 6S RNA:RNAP complexes. Our findings indicate that A. aeolicus 6S RNA function in its hyperthermophilic host is mechanistically identical to that of other bacterial 6S RNAs. The use of artificial pRNA variants, designed to disrupt helix P2 from the 3;prime&-CB instead of the 5;prime&-CB but preventing formation of the CBC helix, indicated that the mechanism of pRNA-induced RNAP release has been evolutionarily optimized for transcriptional pRNA initiation in the 5;prime&-CB.DFG (SPP 1258 and IRTG 1384) to RKH, by the DFG (SFB 902 A2) to EDF and the Spanish Ministry of Economy and Competitiveness (BFU2011-23645) to M.S.Peer Reviewe

Cyanoketene: the microwave spectrum and structure of an unstable molecule

Abstract The unstable molecule cyanoketene has been prepared by pyrolysis in a flow system, and the microwave spectra of five isotopic species, a-and b-type, have been measured in the frequency range from 8 to 40 GHz. Precise rotational constants and centrifugal distortion parameters up to the sixth order were obtained. The molecule has been shown to be planar, and a reliable structure was derived. Also the N -quadrupole coupling constants and the dipole moment components have been determined. The results could be a basis for interstellar spectroscopy of this molecule