A Review of Issues Affecting the Efficiency of Decision Making in the NICE Single Technology Appraisal Process.

BACKGROUND: Escalating demands upon the National Institute for Health and Care Excellence's (NICE's) Single Technology Appraisal (STA) programme require a 2.5-times increase upon 2015 capacity by 2020. This additional strain on committee resources threatens to compromise the rigour of the STA process. In 2018, NICE introduced changes to the appraisal process, aiming to expedite final decisions, including consultation opportunities prior to the company's evidence submission, a 'Technical Engagement' stage prior to the first committee meeting, and powers for committee chairs to recommend technologies without a second formal meeting. OBJECTIVE: This study reviews recent STAs and aims to understand why appraisals require multiple meetings, and whether recent reforms can address the underlying issues. METHODS: NICE STAs published between January 2010 and January 2018 were reviewed, excluding updates or re-considerations. Data on cost, clinical, and decision-making outcomes from 146 appraisals were extracted and analysed thematically. RESULTS: Drugs for advanced cancers were least likely to be recommended (28/43 [65.1%] vs 71/74 [96%] for non-cancer) and took longer (2.36 meetings for a final decision vs 1.97 for non-cancer). The academic review increased upon the company's base-case incremental cost-effectiveness ratio by a median of 32.7%. Eighty-four technologies (57.5%) received a negative preliminary recommendation, deferring a final decision by an average of 142 days. Of these, 85.1% were not considered cost-effective. Uncertainty in economic (34.3%) and clinical (22.3%) data also prevented a positive decision. The majority (72.6% [61/84]) of negative preliminary decisions were overturned following further committee discussion; important considerations were Patient Access Schemes, decision optimisation, and the Cancer Drugs Fund. CONCLUSIONS: Value considerations are the primary driver of negative preliminary recommendations. It is unclear if new opportunities for additional interaction between NICE, review groups, and manufacturers will meaningfully improve the efficiency of the appraisal process, particularly given the proportion of technologies requiring further committee discussion for decision optimisation or admission into the CDF.

Total hip replacement and hemiarthroplasty in mobile, independent patients with a displaced intracapsular fracture of the femoral neck: a seven- to ten-year follow-up report of a prospective randomised controlled trial.

We reviewed the seven- to ten-year results of our previously reported prospective randomised controlled trial comparing total hip replacement and hemiarthroplasty for the treatment of displaced intracapsular fracture of the femoral neck. Of our original study group of 81 patients, 47 were still alive. After a mean follow up of nine years (7 to 10) overall mortality was 32.5% and 51.2% after total hip replacement and hemiarthroplasty, respectively (p = 0.09). At 100 months postoperatively a significantly greater proportion of hemiarthroplasty patients had died (p = 0.026). Three hips dislocated following total hip replacement and none after hemiarthroplasty. In both the total hip replacement and hemiarthroplasty groups a deterioration had occurred in walking distance (p = 0.02 and p < 0.001, respectively). One total hip replacement required revision compared with four hemiarthroplasties which were revised to total hip replacements. All surviving patients with a total hip replacement demonstrated wear of the cemented polyethylene component and all hemiarthroplasties had produced acetabular erosion. There was lower mortality (p = 0.013) and a trend towards superior function in patients with a total hip replacement in the medium term.

The success of management with the Pavlik harness for developmental dysplasia of the hip using a United Kingdom screening programme and ultrasound-guided supervision.

We present the results of treatment of developmental dysplasia of the hip in infancy with the Pavlik harness using a United Kingdom screening programme with ultrasound-guided supervision. Initially, 128 consecutive hips in 77 patients were reviewed over a 40-month period; 123 of these were finally included in the study. The mean age of the patients at the start of treatment was five weeks (1 to 12). All hips were examined clinically and monitored with ultrasound scanning. Failure of treatment was defined as an inability to maintain reduction with the harness. All hips diagnosed with dysplasia or subluxation but not dislocation were managed successfully in the harness. There were 43 dislocated hips, of which 39 were reducible, but six failed treatment in the harness. There were four dislocated but irreducible hips which all failed treatment in the harness. One hip appeared to be successfully treated in the harness but showed persistent radiological dysplasia at 12 and 24 months. Grade 1 avascular necrosis was identified radiologically in three patients at 12 months.

The prognosis of fasciectomy for abductor digiti minimi and pretendinous cords in Dupuytren's disease of the little finger.

Thirty-nine consecutive patients with little finger Dupuytren's contracture underwent open fasciectomy. Diseased abductor digiti minimi (ADM) pretendinous (PT) cords were identified. The mean pre-operative PIPJ contracture was 77 degrees in the PT group and 66 degrees in the ADM group. Mean residual deformity was 12 degrees in the PT group and 9 degrees in the ADM group. At six months, ten out of 27 patients had developed a recurrent deformity in the PT group (mean 24 degrees ) and seven out of 11 in the ADM group (mean 18 degrees ). There was no statistically significant difference between the two groups at any stage. Dupuytren's contracture of the little finger is as a result of an ADM cord in 29% of cases. In this series it led to an isolated contracture of the PIPJ in the majority of cases and rarely affected the MCPJ. Disease of the ADM cord was not associated with a difference in contracture or prognosis compared to a PT cord.

The effectiveness of physiotherapist-led arthroplasty follow-up clinics.

INTRODUCTION: The conventional job descriptions of professionals within the NHS need to evolve in order to meet increasingly stringent targets and demands. One innovation is the introduction of a physiotherapist-led arthroplasty follow-up clinic. We present an audit of 1000 appointments to this clinic. PATIENTS AND METHODS: A total of 865 patients were seen with 933 arthroplasties over an 8-month period; 135 appointments were not attended. Prospective data were collected at each attendance. RESULTS: Less than 7.5% of patients required re-referral to an orthopaedic consultant, of which 36% were for consideration for further joint replacement. The cost of a physiotherapy appointment was pound4.97 compared to pound5.04 for a traditional orthopaedic assessment. By reducing the number of follow-up patients seen in orthopaedic clinics, we estimate that each consultant would be able to see two additional new patients per week. CONCLUSIONS: Assessment of arthroplasty follow-up outside of the traditional orthopaedic clinic setting is a time-effective alternative; however, the cost-benefit and educational impact is less clear.

The progression of arthritis following lateral unicompartmental knee replacement.

In order to aid patient selection we have analysed the radiological progression of arthritis in the retained compartments following lateral unicompartmental knee replacement (UKR). Patients undergoing lateral UKR (St Georg Sled, Waldemar Link) between 1988 and 1999 were assessed. Radiographs taken post-operatively within 8 weeks and at 5 years were assessed. OA was classified using both the Altman and Ahlbach scoring systems. Identifying information on each radiograph was obscured so that the observer was blinded. Each radiograph was reviewed twice to assess intra-observer variability. Patients were assessed clinically using the Bristol Knee Score (BKS) at 1 and 5 years post-operation. Reproducibility for the Ahlbach systems was shown to be very good (kappa = 0.86) and the Altman moderate (kappa = 0.41). Thirty-two lateral UKRs were assessed at 5 years. Six out of 32 of the knees assessed showed definite progression of OA on the Ahlbäch score in the retained medial compartment and 11 out of 32 on the Altman. There was a statistically significant increase in the grade of OA, as assessed by both systems, at 5 years as compared to the post-operative radiograph (p < 0.001). The definite progression group had a mean BKS 10 points lower at 5 years. Six patients required revision to TKR for progression of arthritis in the retained compartments. Lateral compartment UKR can be a very successful procedure, but there is a greater rate of progression of arthritis in the retained medial compartment than following medial UKR.

Can a urinary tract symptom score predict the development of postoperative urinary retention in patients undergoing lower limb arthroplasty under spinal anaesthesia? A prospective study.

INTRODUCTION: There is no general consensus amongst orthopaedic surgeons on how best to manage the urinary tract and its complications after lower limb arthroplasty. This prospective audit investigates whether postoperative urinary retention can be predicted pre-operatively using the validated International Prostate Symptom Severity score (IPSS). PATIENTS AND METHODS: A total of 182 patients undergoing lower limb arthroplasty under spinal anaesthetic were given the IPSS questionnaire to complete pre-operatively and an audit into numbers catheterised postoperatively was performed. RESULTS: Overall, 69% of males and 39% of females required catheterisation. Following logistic regression analysis there was 0.85 predicted probability that males over 70 years would require catheterisation. The IPSS score was not useful in predicting retention in either sex at any age. CONCLUSIONS: We propose that all males over 70 years undergoing this type of surgery should be catheterised pre-operatively and all other patients should be catheterised postoperatively with close monitoring of bladder volumes to prevent established urinary retention.

Population structure of harbour porpoises Phocoena phocoena in the seas around the UK and adjacent waters.

The population structure of harbour porpoises from British and adjacent waters was studied by examining variability in a 200 bp (base pair) section of the control region of mitochondrial DNA (mtDNA) extracted from 327 animals. This region contained 20 variable sites giving rise to 24 different haplotypes. Mean nucleotide diversity between all pairs of haplotypes was 0.81% (range 0-4%). The most common haplotype occurred in 63% of the samples and was recorded in all geographical areas; several other haplotypes were present in two or more of the sampling locations. This suggests considerable historical interconnections among populations, probably through gene flow. However, there were significant differences (p < 0.05) as determined by AMOVA (Analysis of Molecular Variance, Excoffier et al. 1992), between porpoises from the northern and southern North Sea, and between the northern North Sea and the Celtic/Irish Sea. The differences were predominantly due to variation among females. This sex-related difference in population genetic structure suggests that males disperse more than females. This has important consequences for evaluating the consequences of incidental catches of porpoises by fisheries in these seas since there may be a greater impact on local populations than is implied by simple calculations of mortality.

Studies on the putative role of gamma-glutamyl transpeptidase in intestinal transport of amino acids in Atlantic salmon.

The gamma-glutamyl cycle is considered to function in the membrane transport of amino acids, particularly glutamine and cysteine. When groups of Atlantic salmon were fed either a control diet containing 45% crude protein or an amino acid diet (of similar overall amino acid composition but containing elevated levels of glutamine and cysteine) for 16 weeks, weight gains were significantly greater in the former group than in those given the amino acid diet. There were no significant differences between treatments in gamma-glutamyl transpeptidase (GT) activity in the proximal intestine; in distal intestine there was significantly more activity in control fish. Mean levels of GSH were higher in tissues (pyloric caeca, distal intestine and kidney) of amino acid diet fish than in those of control fish. Glutamine was less effective as a gamma-glutamyl acceptor than several other amino acids when tested with salmon caecal GT. There were no morphological adaptations to the two feeds. Nutrient uptake studies showed an increased uptake of glutamine, but decreased uptakes of proline and methionine in proximal intestine of salmon fed amino acid diet. Much the greater part of the glutamine uptake, even at high concentrations was shown to be by Na+ dependent processes. There is no evidence that GT itself is Na+ dependent. The results do not support the view that the gamma-glutamyl cycle and GT in particular are involved in the transport of amino acids in the intestine and are discussed in this context.

Dietary requirements of rainbow trout for tryptophan, lysine and arginine determined by growth and biochemical measurements.

Three separate studies were performed to determine the dietary requirements of rainbow troutSalmo gairdneri for tryptophan (Trp), lysine (Lys) and arginine (Arg) from both growth and biochemical data. The growth studies were carried out over a 12 week period. From graphical plots of % mean weight gain against % amino acid in diet the following requirement values were obtained, Trp 0.25% diet (0.4% dietary crude protein); Lys 1.9% diet (4.3% dietary protein); and Arg 1.6-1.8% diet (3.6-4% dietary protein). Plasma and liver amino acid concentrations measured 20h after feeding did not prove useful for determination of requirement values. Hepatic activities of Trp pyrrolase (TP), Lys α ketoglutarate reductase (LKGR) and arginase were not significantly affected by varying levels of Trp, Lys and Arg respectively in the diet. TP has a cytosolic location and a Km of 0.2 mM for Trp; LKGR is mitochondrial and the Km for Lys is 7.3 mM; arginase is also mitochondrial and has a Km of 4.9 mM for arginine. Measurements of expired(14)CO2, after injection of a tracer dose of(14)C amino acid, did allow estimates of requirement levels to be made. The values obtained from the oxidation studies reinforced the values obtained from the growth data but were not precise enough to justify using this method on its own.

Metabolic effects of feeding a high protein/low carbohydrate diet as compared to a low protein/high carbohydrate diet to rainbow troutSalmo gairdneri.

Groups of trout were fed either a high protein/low carbohydrate (HP/LC) or a low protein/high carbohydrate (LP/HC) diet for 16 weeks. Fish fed the HP/LC diet had significantly higher levels of protein, ninhydrin positive material and tryptophan in plasma as well as lipid and protein in liver, but lower levels of glucose in plasma, glycogen in liver and a lower hepatosomatic index compared with fish fed the LP/HC diet. There were no differences concentrations of tryptophan or serotonin in the brain of fish fed the different diets. Fish fed the HP/LC diet had significantly lower activities of glycolytic enzymes but higher activities of gluconeogenic enzymes compared with the group fed the LP/HC diet. Those enzymes measured concerned with the TCA cycle or initiating amino acid catabolism were generally unaffected by diet although activities of threonine dehydrogenase, alanine aminotransferase and glutamate dehydrogenase were higher in those fish fed the HP/LC diet. The data suggest that rainbow trout show little adaptation in activities of amino acid catabolising enzymes to variations in dietary protein intake.

Intracellular distribution of tricarboxylic acid cycle enzymes in liver of rainbow trout Salmo gairdneri.

The intracellular distribution of enzymes of the TCA cycle was investigated in liver of rainbow trout. All enzymes of the cycle apart from succinyl thiokinase were detected. Citrate synthase, alpha-ketoglutarate dehydrogenase and succinate dehydrogenase were wholly mitochondrial. Fumarase, malate dehydrogenase, aconitase and NADP-isocitrate dehydrogenase were detected in both cytosol and mitochondria.

The effect of dietary lysine levels on growth and metabolism of rainbow trout (Salmo gairdneri).

Groups of rainbow trout (Salmo gairdneri; mean weight 5 g) were given diets containing 10, 12, 14, 17, 21, 24 and 26 g lysine/kg diet for 12 weeks. By analysis of the growth values the dietary requirement of lysine in this experiment was found to be 19 g/kg diet. A similar requirement value was obtained from a dose-response curve of expired 14CO2 (following an intraperitoneal injection of L-[U-14C]lysine) v. dietary lysine concentration. Liver concentrations of total lipid and carnitine and activities of lysine-alpha-ketoglutarate reductase (saccharopine dehydrogenase (NADP+, lysine-forming), EC 1.5.1.8) in the liver were not significantly different in fish from the different dietary treatments. Hepatosomatic index, however, was higher in those fish given low levels of dietary lysine.

The effects of dietary tryptophan levels on growth and metabolism of rainbow trout (Salmo gairdneri).

Groups of rainbow trout (Salmo gairdneri) (mean weight 14 g) were given diets containing 0.8, 1.3, 2, 3, 4 or 6 g tryptophan/kg diet for 12 weeks. By analysis of the growth results, the dietary requirement of tryptophan was found to be 2.5 g/kg diet (equivalent to 50 mg/kg biomass per d). Carbon dioxide expired by trout following intraperitoneal injection of [14COOH]tryptophan contained little radioactivity when dietary tryptophan level was low but, above 2.0 g/kg diet, it increased rapidly with increasing dietary tryptophan level. The break point in the dose-response curve did not, however, coincide with that from the growth results. Changes in concentrations of free tryptophan in blood and liver and activity of hepatic tryptophan pyrrolase (EC 1. 13. 11. 11) in response to changes in dietary tryptophan concentration did not provide reliable indicators for quantifying dietary requirement. Unlike the situation in mammals, blood tryptophan was not protein-bound to any appreciable extent. Tryptophan pyrrolase of trout has properties which suggest it has no apoenzyme form. In fish given adequate levels of tryptophan injected intraperitoneally with a tracer dose of [14COOH]tryptophan, 60% of the dose was incorporated into body protein within 1 d. The turnover of the label in this protein is very slow. Those trout given diets deficient in tryptophan suffered from severe scoliosis and lordosis as well as having increased liver and kidney levels of calcium, magnesium, sodium and potassium.

Methionine metabolism in rainbow trout fed diets of differing methionine and cystine content.

The metabolism of methionine was studied in rainbow trout fed diets containing different levels of methionine and cystine. Growth data indicated that methionine requirement was between 0.5 and 1% dry diet in the absence of dietary cystine, but 0.5% was adequate when dietary cystine was 2%. In fish fed diets deficient in sulfur-containing amino acids, elevated hepatic activities of glutathione reductase were found, whereas glutathione peroxidase and glutathione levels were unaffected. Plasma and liver concentrations (18 hours after feeding) of methionine and cystine were affected by dietary methionine, but dietary cystine had little effect. Cystine appeared to be converted to taurine in the liver. In fish injected intraperitoneally with [14COOH]- and [14CH3]methionine, over 24 hours the carboxyl group was oxidized more than the methyl group and more was incorporated into protein. However, much more of the methyl group was incorporated into the lipid fraction. The results suggest the operation of the transsulfuration pathway of methionine catabolism. Oxidation of methionine was related to its concentration in the tissues, and little affected by dietary cystine. A 28-day experiment on the metabolism of injected [14COOH]methionine showed that its turnover was slow, and much of the radioactivity was associated with protein.

Tissue distribution, uptake, and requirement for alpha-tocopherol of rainbow trout (Salmo gairdneri) fed diets with a minimal content of unsaturated fatty acids.

The metabolism of and requirements for alpha-tocopherol in rainbow trout fed diets containing 1% linolenic acid as sole source of unsaturated fat and graded levels of tocopherol (0.06-10 mg/100 g) were examined. Fish grew 5-fold over a 16-week period. In liver, tocopherol was concentrated in mitochondria with little in cytosol. Orally administered [3H]-tocopherol was rapidly taken up by plasma and liver but uptake into erythrocytes and white muscle was much slower; in most tissues radioactivity reached a plateau after about 3 days but in red muscle radioactivity increased over a 10-day period. Activities of enzymes that prevent free radical initiated tissue damage did not change in tocopherol deficiency. Tocopherol-deficient trout had no gross or subcellular pathologies even though liver and muscle were severely depleted of the vitamin. Ascorbic acid-stimulated lipid peroxidation in liver organelles indicated a tocopherol requirement of 2-3 mg/100 g diet; the molar ratios of polyunsaturated fatty acids to tocopherol in livers of trout fed diets lacking or supplemented with tocopherol (100 mg/100 g) were 980 and 170, respectively.

Karyology: vaccine manufacturers' views.

Chromosomal analyses and life span studies of WI-38 cell cultures used for vaccine production at the Connaught Laboratories Ltd will be described. Twenty cultures derived from the same seed lot and 25 cultures derived from different starter cultures were analyzed. Karyology tests at population doublings 31 and higher were within acceptable limits. The WI-38 cells reached a finite lifespan of approximately 65 population doublings. Normal growth characteristics were observed within 2/3 of the finite lifespan, i.e. until population doubling 40. The finite lifespan of MRC-5 was found to be 75 population doublings, with normal growth pattern until passage 50. The karyology test results, cell yields and the finite lifespans indicated that these cells could be used as substrates for vaccine production at higher passage levels than previously suggested. Using serially subcultivated cells at higher passage levels would make possible an increase in the volume of vaccine from existing cell seed and would also result in significant reduction in production costs.

Some studies on the biosynthesis of ubiguinone, isoprenoid alcohols, squalene and sterols by marine invertebrates.

The ability of fourteen marine invertebrates to utilize [(14)C]mevalonate for the biosynthesis of isoprenoid compounds was investigated. Several of the animals, in particular crustaceans, bivalve molluscs, a coelenterate and a sponge, were unable to synthesize squalene and sterols, whereas gastropod molluscs, echinoderms, an annelid and a sponge could. Regardless of sterol-synthesizing ability the animals (with the exception of a sponge) always made dolichol and ubiquinone, and thus a specific block in squalene and sterol synthesis was indicated in some animals. Radioactivity accumulated in relatively large amounts in farnesol and geranylgeraniol in those animals incapable of making sterols.