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

Predicting Forage Provision of Grasslands Across Climate Zones by Hyperspectral Measurements

The potential of grasslands’ fodder production is a crucial management measure, while its quantification is still laborious and costly. Remote sensing technologies, such as hyperspectral field measurements, enable fast and non-destructive estimation. However, such methods are still limited in transferability to other locations or climatic conditions. With this study, we aim to predict forage nutritive value, quantity, and energy yield from hyperspectral canopy reflections of grasslands across three climate zones. We took hyperspectral measurements with a field spectrometer from grassland canopies in temperate, tropical and semi-arid grasslands, and analyzed corresponding biomass samples for their quantity (BM), metabolizable energy content (ME) and metabolizable energy yield (MEY). Three machine learning algorithms were used to establish prediction models for single and across climate regions. The normalized root mean squared error (nRMSE) for ME, BM and MEY varied between 0.12 – 0.19, 0.14 – 0.21, and 0.15 – 0.21, respectively. The ME trans-climatic model showed the best accuracy compared to the local models. Trans-climatic model predictions of climate-specific data, decrease in accuracy to 0.16 – 0.21, 0.17 – 0.24, and 0.19 – 0.28 for ME, BM and MEY compared to predictions with climate-specific models. Trans-climatic models with feed-forward neural networks showed similar performance for ME but higher accuracies for BM and MEY predictions. The trans-climatic models generally showed good performance for forage nutritive value and forage provision. Our results suggest that models based on hyperspectral measurements offer great potential to assess or even map the forage nutritive value of grasslands across climate zones

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

Species boundaries in Philippine montane forest skinks (Genus Sphenomorphus): three new species from the mountains of Luzon and clarification of the status of the poorly known S. beyeri, S. knollmanae, and S. laterimaculatus

Recent collections of Sphenomorphus beyeri Taylor 1915 from the type locality (Mt. Banahao, Luzon Isl., Philippines) serve as the basis for a thorough analysis of topotypic variation in external morphology within the species, and allow for detailed comparisons to other taxa. We clarify the taxonomic status of S. beyeri with respect to other, phenotypically similar species and evaluate species boundaries between allopatric populations referred to this taxon. The high elevation (1400–1700 m) population of Sphenomorphus (Brown et al., 1995a) from the Zambales Mountains and Bataan Peninsula of Luzon Island (previously referred by us to S. beyeri) is a new species that we describe here. We also describe two additional new species from the isolated, high elevation (1650–1750 m) forests of the Northern Cordillera and the Sierra Madre of Luzon, specimens of both of which had been previously identified as S. beyeri. All three new species differ from each other and all other Sphenomorphus species by scalation, body size, and coloration and all have non-overlapping distributions, associated with separate, isolated, geological components of Luzon Island. In this paper we also formally redescribe S. beyeri on the basis of a large series of specimens from the type locality (Mt. Banahao, southern Luzon Island) that we have accumulated over the last 15 years. We place S. knollmanae Brown, Ruedas, and Ferner 1995 in synonymy with S. laterimaculatus (Brown and Alcala, 1980) and redescribe the latter species on the basis of the holotype and 20 additional newly collected specimens from six localities on the Bicol Peninsula of Luzon Island and Marinduque Island. These and other data suggest that species boundaries in Philippine Sphenomorphus are poorly understood and that taxonomic diversity is substantially underestimated and in need of comprehensive taxonomic review

Clinical presentation and prognostic indicators in 100 adults and children with neurofibromatosis 1 associated non-optic pathway brain gliomas

Type 1 Neurofibromatosis (NF1) is a common autosomal dominant condition, with a major impact on the nervous system, eye, bone, and skin, and a predisposition to malignancy. At present it is not possible to predict clinically or on imaging, whether a brain tumour will remain indolent or undergo high-grade change. There are no consensus guidelines on the follow-up of non-optic pathway glioma (non-OPG) tumours in NF1. One hundred patients from the National NF1 Service with generalised NF1 and a diagnosis of non-OPG glioma were followed up for a median time of 63 months after glioma detection. Forty-two patients underwent surgical intervention. Ninety-one percent (38) of those requiring surgery did so within 5 years of diagnosis of glioma. Serial neuroimaging was undertaken in 88 patients. In 66 (75%), the lesion on the scan was stable or had improved at follow-up. High-grade lesions were present in five patients and were strongly associated with tumours in the thalamus (p = 0.001). Five patients died during follow-up. The diagnosis of high-grade glioma had a HR of 99.7 (95% CI 11.1-898.9, p < 000.1) on multivariate Cox regression to evaluate predictive factors related to death. In our cohort of 100 patients with NF1, we have shown that tumours in the thalamus are more likely to be associated with radiological progression, high-grade tumours, and surgical intervention. As a result of this finding, heightened surveillance with more frequent imaging should be considered in thalamic involvement. We have also demonstrated that over 40% of patients underwent surgery, and did so within 5 years of tumour diagnosis. Serial imaging should be undertaken for at the very least, 5 years from tumour detection

Preventable deaths involving opioids in England and Wales, 2013–2022: a systematic case series of coroners’ reports

Background Opioid deaths have increased in England and Wales. Coroners’ Prevention of Future Deaths reports (PFDs) provide important insights that may enable safer use and avert harms, yet reports implicating opioids have not been synthesized. We aimed to identify opioid-related PFDs and explore coroners’ concerns to prevent future deaths. Methods In this systematic case series, we screened 3897 coronial PFDs dated between 01 July 2013 and 23 February 2022, obtained by web scraping the UK’s Courts and Tribunals Judiciary website. PFDs were included when an opioid was implicated in the death. Included PFDs were descriptively analysed, and content analysis was used to assess concerns reported by coroners. Results Opioids were involved in 219 deaths reported in PFDs (5·6% of PFDs), equating to 4418 years of life lost (median 33 years/person). Morphine (29%), methadone (23%) and diamorphine (16%) were the most common implicated opioids. Coroners most frequently raised concerns regarding systems and protocols (52%) or safety issues (15%). These concerns were most often addressed to National Health Service (NHS) organizations (51%), but response rates were low overall (47%). Conclusions Opioids could be used more safely if coroners’ concerns in PFDs were addressed by national organizations such as NHS bodies, government agencies and policymakers, as well as individual prescribing clinicians

Drug–drug Interaction between Pravastatin and Gemfibrozil (Antihyperlipidemic) with Gliclazide (Antidiabetic) in Rats

Diabetes mellitus is a condition of increased blood glucose level in the body. Antihyperlipidemic drugs like statins and fibrates are widely used for prophylactic treatment in dyslipideamia and atherosclerosis. Diabetic dislipidemia exists with increased triglycerides, low HDL and high LDL levels. Hence, with oral hypoglycemic drugs, the addition of a lipid-lowering drug is necessary for controlling dislipidemia. In such a situation, there may be chances of drug–drug interactions between antidiabetic and antihyperlipidemic drugs. The present study is planned to evaluate the safety of gliclazide (antidiabetic) in the presence of pravastatin and gemfibrozil (antihyperlpidemic) in rats. Studies in normal and alloxan-induced diabetic rats were conducted with oral doses of gliclazide and their combination with pravastatin and gemfibrozil, with an adequate washout period in between the treatments. Blood samples were collected in rats by retroorbital puncture at 0, 1, 2, 3, 4, 6, 8, 10 and 12 h. All the blood samples were analyzed for glucose by GOD –POD. Gliclazide (½ TD) produced hypoglycemic activity in normal and diabetic rats, with peak activity at 2 and 8 h. Pravastatin (TD) + gemfibrozil (TD) combination treatment increased the hypoglycemic effect of gliclazide in normal rats or diabetic rats when administered together. The interaction observed due to inhibition of both the enzymes (CYP 450 2C9 and CYP 450 3A4) responsible for the metabolism of gliclazide showed increased half-life, which was seen in the present study. Because concomitant administration of gliclazide with provastatin and gemfibrozil in diabetes is associated with atherosclerosis, it should be contraindicated or used with caution

Contested resources: unions, employers, and the adoption of new work practices in US and UK telecommunications

The pattern of adoption of high-performance work practices has been explained in terms of strategic contingency and in terms of union presence. We compare the post-deregulation/privatization changes in work practice at AT&T, Bell Atlantic and British Telecom. On the basis of these cases, we argue that the choice of new work practices should be understood as a consequence not only of the company's resources or changes in its environment, nor of a simple union presence, but also as a consequence of the practices' effects on union power, the nature of the union's engagement, and the union's strategic choices