Autologous Chondrocyte Implantation with Chondrosphere for Treating Articular Cartilage Defects in the Knee: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Chondrosphere (Spherox) is a form of autologous chondrocyte implantation (ACI). It is licensed for repair of symptomatic articular cartilage defects of the femoral condyle and the patella of the knee with defect sizes up to 10 cm2 in adults. In a single technology appraisal (STA) [TA508] undertaken by the National Institute of Health and Care Excellence (NICE), Warwick Evidence was the Evidence Review Group (ERG) invited to independently review the evidence submitted by the manufacturer, Co.Don. The clinical effectiveness data came from their COWISI randomised controlled trial (RCT), which compared Chondrosphere with microfracture (MF). The timing of this appraisal was unfortunate given that MF was no longer the most relevant comparator because NICE had contemporaneously published guidance approving ACI in place of MF. Moreover, the COWISI RCT enrolled mostly patients with small defect sizes. Evidence of clinical effectiveness for Chondrosphere used in people with larger defect size came from another RCT, which compared three doses of Chondrosphere and that by design could not provide evidence comparing Chondrosphere to any other forms of ACI. To estimate the relative clinical performance of Chondrosphere versus other ACI, Co.Don conducted an indirect treatment comparison by network meta-analyses (NMA). The NMA was flawed in that the distribution of population characteristics that are effect modifiers greatly differed across the treatment comparisons of the network. The ERG questioned both the appropriateness of the NMA and the validity of the resulting estimates. Co.Don estimated the cost-effectiveness of Chondrosphere using a lifetime Markov model with all patients receiving the first repair during the first cycle of the model then moving into one of three health states: success, no further repair (NFR), or a second repair, if necessary. Subsequent to the first cycle, those who were a success either remained a success or moved to second repair. All those in NFR remained in NFR. The cost-effectiveness of Chondrosphere compared to other ACI forms relied on the clinical effectiveness estimates of success and failure rates obtained from the company's indirect comparisons, the validity of which the ERG questioned. The company revised cost-effectiveness estimates for Chondrosphere versus MF and for Chondrosphere versus matrix-applied characterised autologous cultured chondrocyte implant (MACI) were £4360 and around £18,000 per quality-adjusted life year gained, respectively. NICE recommended ACI using Chondrosphere for treating symptomatic articular cartilage defects of the femoral condyle and patella of the knee in adults only if certain requirements were met.

Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes: systematic review and economic evaluation.

BACKGROUND: Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight and increasing physical activity. Even modest weight loss can improve control of blood glucose. If drug treatment is necessary, the drug of first choice is metformin. However, some people cannot tolerate metformin, which causes diarrhoea in about 10%, and it cannot be used in people with renal impairment. This review appraises three of the newest class of drugs for monotherapy when metformin cannot be used, the sodium-glucose co-transporter 2 (SGLT2) inhibitors. OBJECTIVE: To review the clinical effectiveness and cost-effectiveness of dapagliflozin (Farxiga, Bristol-Myers Squibb, Luton, UK), canagliflozin (Invokana, Janssen, High Wycombe, UK) and empagliflozin (Jardiance, Merck & Co., Darmstadt, Germany), in monotherapy in people who cannot take metformin. SOURCES: MEDLINE (1946 to February 2015) and EMBASE (1974 to February 2015) for randomised controlled trials lasting 24 weeks or more. For adverse events, a wider range of studies was used. Three manufacturers provided submissions. METHODS: Systematic review and economic evaluation. A network meta-analysis was carried out involving the three SGLT2 inhibitors and key comparators. Critical appraisal of submissions from three manufacturers. RESULTS: We included three trials of dapagliflozin and two each for canagliflozin and empagliflozin. The trials were of good quality. The canagliflozin and dapagliflozin trials compared them with placebo, but the two empagliflozin trials included active comparators. All three drugs were shown to be effective in improving glycaemic control, promoting weight loss and lowering blood pressure (BP). LIMITATIONS: There were no head-to-head trials of the different flozins, and no long-term data on cardiovascular outcomes in this group of patients. Most trials were against placebo. The trials were done in patient groups that were not always comparable, for example in baseline glycated haemoglobin or body mass index. Data on elderly patients were lacking. CONCLUSIONS: Dapagliflozin, canagliflozin and empagliflozin are effective in improving glycaemic control, with added benefits of some reductions in BP and weight. Adverse effects are urinary and genital tract infections in a small proportion of users. In monotherapy, the three drugs do not appear cost-effective compared with gliclazide or pioglitazone, but may be competitive against sitagliptin (Januvia, Boehringer Ingelheim, Bracknell, UK). FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Poor readers' use of orthographic information in learning to read new words: a visual bias or a phonological deficit?

In this study, we examined the ability of 11-year-old poor readers and reading age controls to learn new print vocabulary. It was found that the poor readers were slower than the controls to learn to read a set of nonwords accurately but that, when asked to pick out the nonwords in a visual recognition memory task, they reached criterion much more quickly than did the controls. However, when the groups were compared on auditory recall of the items being learned, the poor readers were at a disadvantage. Thus, the poor readers developed a visual store for the nonwords more quickly than did the controls but were slower to establish phonological representations for the nonwords. It was concluded that the poor readers were slower to establish a form of sight word reading that was well underpinned in memory by connections between the letters in the spelling and the phonemes in the pronunciation, suggesting that they had a greater reliance on an orthographic-semantic pathway in word recognition than did the controls.

Toward a resolution of inconsistencies in the phonological deficit theory of reading disorders: phonological reading difficulties are more severe in high-IQ poor readers.

This study examined whether high- and low-IQ poor readers differed in patterns of reading performance. Ten-year-old poor readers with IQ scores of 110 and higher showed difficulty in taking a phonological approach to reading, failing to show an advantage in reading high-frequency regular versus irregular words and showing impaired nonword reading accuracy for their reading age. However, poor readers with IQ scores of 90 and below showed a more phonological approach to reading, with better reading of regular than irregular words of both high and low frequency, and with nonword reading skills slower than, but as accurate as, those of reading-age controls. We concluded that the high-IQ poor readers experienced difficulty in taking a phonological approach to reading, whereas the low-IQ poor readers had much less marked phonological problems, supporting Stanovich's phonological-core variable-difference model.

When phonology fails: orthographic neighbourhood effects in dyslexia.

Both cerebral hemispheres contain phonological, orthographic and semantic representations of words, however there are between-hemisphere differences in the relative engagement and specialization of the different representations. Taking orthographic processing for example, previous studies suggest that orthographic neighbourhood size (N) has facilitatory effects in the right but not the left hemispheres. To pursue the nature of this asymmetric N effect, in particular whether there are individual differences in such specialisation, we examined N in a case of developmental dyslexia, FM. We first describe the nature of his difficulties, which are mainly severe phonological deficits. Employing the divided visual field paradigm with FM revealed a greater sensitivity in the right than in the left hemisphere to orthographic variables, with a significant inhibitory N effect in the left, but not right hemisphere. Such inhibition, to a lesser degree, was found among a group of adults with dyslexia but not among age-matched normal readers. We argue that enhanced sensitivity to orthographic cues is developed in some cases of dyslexia when a normal, phonology-based left hemisphere word recognition processing is not achieved. The interpretation presented here is cast in terms of differences between people with dyslexia and typical readers that originate in the atypical way in which orthographic representations are initially set up.

Word length, phonemic, and visual similarity effects in poor and normal readers.

Serial order recall for visually and auditorily presented stimuli was examined in a group of 12-year-old poor readers and 7-year-old reading-age controls. With pictorial presentation, the poor readers showed a visual similarity effect, no word length effect, and a smaller phonemic similarity effect than that of controls. However, with visual presentation of printed words and with auditory presentation, poor readers showed word length and phonemic similarity effects of similar magnitude to that of controls. It is concluded that poor readers rely on visual information in tasks where the presented images are highly codable, and where verbal recoding is not obligatory, but that they will make use of phonological coding when the stimuli are not as easily codable visually in memory.

Extrachromosomal nucleic acids in bovine babesia

Two kinds of small extrachromosomal nucleic acid elements were found in the bovine babesias, Babesia bovis and B. bigemina. One element with an apparent size of 5.5 kilobase pairs (kbp) is a double stranded RNA related to virus like particles. Another molecule is a double stranded DNA with a molecular size of about 6.2 kbp. Southern blot comparison of restriction DNA fragments of the latter molecule, which is present in both B. bovis and B. bigemina is described

Action of the pyrrolizidine alkaloid integerrimine in inducing meiotic chromosome aberrations in male mice

A fase S (pré-leptoteno) da meiose masculina de camundongos C3H/HeJ e C57BL/6, foi exposta às doses 6,25; 12,50; 25 e 50 mg/kg de peso corpóreo do alcalóide pirrolizidínico integerrimina. Näo observamos efeitos sobre as aberraçöes cromossômicas, estruturais e numéricas, analisadas em diacinese/metáfase I