Cone-beam computed tomographic evaluation to estimate the prevalence of palatogingival groove in the maxillary anterior teeth and its radiographic characteristics: An institutional retrospective study.

Aim: The purpose of the study was to radiographically evaluate the prevalence of palatogingival groove (PG) in the East Indian population in the maxillary anterior teeth in different genders, its unilateral/bilateral presentation, classified based on its radiographic characteristics, to determine the prevalence of different types, which could help in future treatment planning. Study Design: The design of the study was a retrospective study. Materials and Methods: Analysis of 429 maxillary anterior teeth (144 central incisors, 145 lateral incisors, and 139 canines) in 72 cone-beam computed tomography scans was done (31 males and 41 females, mean age 27.3 ± 7.63). Demographic details of patients and characteristics of PG, i.e. location, extension, depth, and type, were recorded. The presence of alveolar bone loss and periapical pathology was noted. Results: An overall prevalence of PG was found to be 2.33% (n = 10), with PG being detected in 2 (1.388%) central incisors, 8 (5.51%) lateral incisors, and 0 (0%) canines. Eight of the patients had a unilateral presence, while one patient reported with bilateral presence, implying a significantly higher predilection of unilateral occurrence (P = 0.02). The prevalence was found to be higher in females (n = 8). The teeth were categorized as either having Type I (6 teeth), Type II (3 teeth), or Type III (1 teeth). Three of the 10 PGs were present in the mesial, six in the mid-palatal, and one in the distal portion of the palatal surface. Conclusions: The prevalence of PG in the maxillary incisors in this cohort is 2.33%. The maxillary lateral incisors are the most affected teeth. Unilateral presentation is more common.

See-through "C": Case series.

Successful endodontic treatment relies upon a thorough knowledge of root canal anatomical variations along with proper diagnosis, treatment planning, and clinical expertise. One of the difficult root canal configurations that are frequently encountered commonly in mandibular second molars is C-shaped root canal. Due to the intricate root canal configuration, it is often difficult to negotiate, debride, and obturate such canals leading to failure of root canal treatment. Understanding the anatomical variation and adequate visualization will enable the clinician to manage these cases effectively. Advanced irrigation and obturation techniques help in managing such anomalous canal configurations. This article presents the management of two different C-shaped root canal configurations under dental operating microscope using thermoplasticized obturation techniques.

An evaluation of elution of leachable components from composite resins after light curing by light emitting diode and halogen light: An in vitro study.

Objectives: The purpose of our study was to determine the amount of eluted triethyleneglycol dimethacrylate (TEGDMA) and to compare the eluted TEGDMA in different composite resins after light curing with conventional halogen light curing unit and light emitting diode (LED). Materials and Methods: The present study was conducted on the two types of composite resins, which were divided equally into four groups - Group I: Denoted as Hybrid-LED, Group II: Denoted as Microhybrid-LED, Group III: Denoted as Hybrid-Halogen Group IV: Denoted as Microhybrid-Halogen. Polymerized specimens of hybrid and microhybrid composite resins were stored in air tight centrifuge tubes at 37°C for 24 h, then extract the monomers in high-performance liquid chromatography (HPLC) grade acetonitrile and water and incubated at 37°C for 24 h. All extracts were analyzed by HPLC. Eluted TEGDMA was detected by ultraviolet detector. The results obtained for TEGDMA were computed and analyzed using the one-way ANOVA and independent samples F-test at significance level 0.05. Results and Conclusions: Elution of TEGDMA from all the samples of Group III (Hybrid-Halogen) was greatest and from Group II (Microhybrid-LED) was lowest. The sequence of TEGDMA elution was Group III > Group I > Group IV > Group II. From our results, we can conclude that the LED light curing unit may be more efficient than standard halogen light curing unit. The extractable quantities of composite resin components should be minimized. Furthermore, all ingredients of a dental composite should be declared by the manufacturers, in order to identify those substances in a product which may cause adverse side effects in patients and dental personnel.

Intensive behavioural interventions based on applied behaviour analysis (ABA) for young children with autism: A cost-effectiveness analysis.

BACKGROUND: The economic and social costs of autism are significant. This study evaluates the cost-effectiveness of early intensive Applied Behaviour Analysis (ABA)-based interventions for autistic pre-school children in the UK. METHODS: A de novo economic analysis was developed in Microsoft Excel comparing early intensive ABA-based interventions compared with treatment as usual (TAU). The analysis used 15.5-year time horizon, with costs and benefits discounted a 3.5%. The model structure was based on cohort structure to capture changes in adaptive behaviour and cognitive ability over time. The analysis was informed by an individual patient data (IPD) meta-analysis of available evidence. RESULTS: Adopting a public sector perspective, early intensive ABA-based therapies were associated with greater incremental costs and greater benefits. When pessimistic assumptions were made regarding the long-term effects of treatment incremental costs were £46,103 and incremental quality-adjusted life years (QALYs) were 0.24, resulting in an incremental cost-effectiveness ratio (ICER) of £189,122 per quality-adjusted life year (QALY). When optimistic assumptions were made about long-term effects, incremental costs were £39,233 with incremental benefits of 0.84 QALYs. The resulting ICER was £46,768 per QALY. Scenario analyses emphasised the importance of assumptions made regarding adult outcomes and type of school attended, both of which significantly affect the results of the analysis. CONCLUSIONS: The results of this economic analysis suggest that early intensive ABA-based interventions are unlikely to represent value for money, based on a £20,000 to £30,000 per QALY threshold typically adopted to inform UK healthcare funding decisions. However, important gaps in the available evidence, limit the strength of the conclusions that can be drawn from the presented analysis. Further research, focusing on the trajectory of autistic children following intervention is likely to be highly beneficial to resolving some of these uncertainties.

Metabolite profiling reveals overexpression of the global regulator, MoLAEA leads to increased synthesis of metabolites in Magnaporthe oryzae.

AIMS: To study the altered metabolic pathways and metabolites produced in overexpression and knockdown mutants of a global regulator named MoLAEA, which was recently found to regulate the expression of the genes involved in secondary metabolism in one of the most destructive plant pathogens, Magnaporthe oryzae. METHODS AND RESULTS: Mass spectrometry-based global untargeted metabolomic profiling was used to identify altered metabolites. Metabolites were extracted from the mutant strains of MoLAEA using two extraction methods viz., aqueous and organic extraction and data acquired using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in positive and negative polarities. Levels of metabolites involved in various biological pathways such as amino acid as well as polyamine biosynthesis, fatty acid and pyrimidine metabolism showed a remarkable change in the mutant strains. Interestingly, metabolites involved in stress responses were produced in higher quantities in the overexpression strain, whereas certain overproduced metabolites were associated with distinctive phenotypic changes in the overexpression strain compared with the wild type. Further, the expression of several genes involved in the stress responses was found to have higher expression in the overexpression strain. CONCLUSIONS: The global regulator MoLAEA is involved in secondary metabolism in the plant pathogen M. oryzae such that the mutant strains showed an altered level of several metabolites involved in the biosynthesis pathways compared with the wild type. Also, metabolites involved in stress responses were overproduced in the overexpression strain and this can be seen in the higher growth in media amended with stress-inducing agents or a higher expression of genes involved in stress response in the overexpression strain compared with the wild type. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report of metabolite profiling relative to the global regulation of secondary metabolism in M. oryzae, where secondary metabolism is poorly understood. It opens up avenues for more relevant investigations on the genetic regulation of several of the metabolites found in the analysis, which have not been previously characterized in M. oryzae.

Carboxylate-Decorated Aggregation of Octanuclear Co4Ln4 (Ln = Dy, Ho, Yb) Complexes from Ligand-Controlled Hydrolysis: Synthesis, Structures, and Magnetic Properties.

One-pot reactions of an asymmetric carboxy-ether-phenol based Schiff base H2L (2-((2-hydroxy-3-methoxybenzylidene)amino)benzoic acid) with selected Ln(NO3)3·nH2O and [Co2(µ-OH2)(O2CCMe3)4(HO2CCMe3)4] (Co2-Piv) in basic MeOH medium resulted in a family of three octanuclear complexes, [CoII4LnIII4L4(µ1,3-Piv)4(µ1,1,3-Piv)2(η1-Piv)2(µ3-OH)4(MeOH)2]·mMeOH·nH2O (Ln = Dy; m = 3, n = 1 (1), Ho; m = 4, n = 0 (2), Yb; m = 3, n = 1 (3)). The coordination aggregates thus obtained were nicely sustained by four ligand anions and eight externally added carboxylate anions showing three different modes of intermetallic connectivity. The options for incorporating different 4f ions in an investigative synthesis, without altering the resulting intermetallic core structure, were successful for the three representative examples. Single-crystal X-ray diffraction studies revealed that the compounds are isostructural and built from two initially formed partial dicubane-type Co2Ln2L2 units. In each of the tetranuclear parts, the metal ion centers are held together by two L2-, two µ3-HO-, three Piv- bridges, one terminal Piv-, and one terminal MeOH. Four carboxylate ends of four L2- units are responsible for connecting two Co2Ln2 units into octanuclear structures. The unique distortion around the CoII centers is achieved from the facile coordination of bigger 4f ions to the adjacent hard OO sites. The distortion is further maintained by the presence of terminal COO- groups from L2-. The dc magnetic susceptibility data revealed ferromagnetic coupling between the CoII and LnIII centers within the series, whereas the ac magnetic susceptibility measurements identified only 1, having a highly anisotropic DyIII ion, as a single-molecule magnet in the absence of any external magnetic field, with an energy barrier Ueff of 12.5 K.

Octanuclear Ni4 Ln4 Coordination Aggregates from Schiff Base Anion Supports and Connecting of Two Ni2 Ln2 Cubes: Syntheses, Structures, and Magnetic Properties.

A family of 3d-4f aggregates have been reported through guiding the dual coordination modes of ligand anion (HL- ) and in situ generated ancillary bridge driven self-assembly coordination responses toward two different types of metal ions. Reactions of lanthanide(III) nitrate (Ln=Gd, Tb, Dy, Ho and Yb), nickel(II) acetate and phenol-based ditopic ligand anion of 2-[{(2-hydroxypropyl)imino}methyl]-6-methoxyphenol (H2 L) in MeCN-MeOH (3 : 1) mixture and LiOH provided five new octanuclear Ni-4f coordination aggregates from two Ni2 Ln2 cubanes. Single-crystal X-ray diffraction analysis reveals that all the members of the family are isostructural, with the central core formed from the coupling of two distorted [Ni2 Ln2 O4 ] heterometallic cubanes [Ni2 Ln2 (HL)2 (µ3 -OH)2 (OH)(OAc)4 ]+ (Ln=Gd (1), Tb (2), Dy (3), Ho (4) and Yb (5)). Higher coordination demand of 4f ions induced the coupling of the two cubes by (OH)(OAc)2 bridges. Variable temperature magnetic study reveals weak coupling between the Ni2+ and Ln3+ ions. For the Tb (2) and Dy (3) analogs, the compounds are SMMs without an applied dc field, whereas the Gd (1) analogue is not an SMM. The observation revealed thus that the anisotropy of the Ln3+ ions is central to display the SMM behavior within this structurally intriguing family of compounds.

Efficacy and Safety of LAMA/LABA Fixed-Dose Combination Therapies in Chronic Obstructive Pulmonary Disease: A Systematic Review of Direct and Indirect Treatment Comparisons.

Background: This literature review assessed comparative efficacy and safety of long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) fixed-dose combinations (FDCs) in patients with COPD and moderate-to-very severe airflow limitation, using evidence from direct (head-to-head) and indirect treatment comparisons. Methods: Two systematic literature reviews were conducted to identify direct comparisons (head-to-head randomized controlled trials [RCTs]) and indirect comparisons (network meta-analyses [NMAs]; indirect treatment comparisons; meta-analyses) in patients with COPD with moderate-to-very severe airflow limitation. Study/Analysis characteristics, eligibility criteria, patient characteristics, and overall conclusions were extracted from relevant publications. The review of indirect comparisons focused on NMAs reporting efficacy outcomes at 12 and 24 weeks of treatment (established durations of symptomatic studies in COPD recommended by regulators). Results: Direct comparisons: Four RCTs that provided head-to-head comparisons of LAMA/LABA FDCs were identified, and these varied in their study design, included patient population and reported endpoints. While some differences in lung function outcomes were noted, where assessed, LAMA/LABA FDCs had comparable efficacy in improving symptoms, health status, exacerbations, and comparable safety profiles. However, the differences in study methodology and patient characteristics between these studies made it difficult to draw generalizable conclusions regarding the comparative effectiveness of LAMA/LABA FDCs from the direct comparisons alone. Indirect comparisons: Six NMAs were identified that reported indirect comparisons between LAMA/LABA FDCs; five of these were within the pre-defined scope of this review. Although the scope of each NMA varied, all five concluded that LAMA/LABA FDCs were generally comparable in terms of lung function improvements, patient-reported outcomes, and safety (where assessed). Conclusion: Although there were some inconsistencies between the outcomes of RCTs and NMAs for lung function, the totality of lung function, symptoms, exacerbations, and safety data suggests that currently available LAMA/LABA FDCs have comparable efficacy and safety in patients with COPD and moderate-to-very severe airflow limitation.

Interventions based on early intensive applied behaviour analysis for autistic children: a systematic review and cost-effectiveness analysis.

BACKGROUND: Early intensive applied behaviour analysis-based interventions are intensive interventions for autistic children that are often delivered on a one-to-one basis for 20-50 hours per week. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of early intensive applied behaviour analysis-based interventions for autistic children, based on current evidence. METHODS: A systematic review and individual participant data meta-analysis were conducted to evaluate the clinical effectiveness of an early intensive applied behaviour analysis-based intervention for autistic children. An economic analysis included a review of existing analyses and the development of a new model. RESULTS: Twenty studies were included in the clinical review. Individual participant data were retrieved from 15 of these studies. Results favoured the interventions when assessing adaptive behaviour after 2 years compared with treatment as usual/eclectic interventions (mean difference 7.00, 95% confidence interval 1.95 to 12.06). In analyses of cognitive ability (intelligence quotient), results favoured the interventions by approximately 10 points after 1 year (mean difference 9.16, 95% confidence interval 4.38 to 13.93) and 2 years (mean difference 14.13, 95% confidence interval 9.16 to 19.10). Evidence for other outcomes was limited and meta-analyses were generally inconclusive. There was no evidence that the effect of the interventions varied with characteristics of the children, but data were limited. Adopting a £30,000 per quality-adjusted life-year threshold, the results of the cost-effectiveness analysis indicate that early intensive applied behaviour analysis-based interventions would need to generate larger benefits or cost savings to be cost-effective. Adopting a public sector perspective and making pessimistic assumptions about long-term effects, the incremental cost-effectiveness ratio for early intensive applied behaviour analysis-based therapy compared with treatment as usual is £189,122 per quality-adjusted life-year. When optimistic assumptions are made, the incremental cost-effectiveness ratio is £46,768 per quality-adjusted life-year. Scenario analyses indicated that these interventions can potentially be cost-effective if long-term improvements persist into adulthood, or if they have significant impact on educational placement. Care should be taken when interpreting these scenarios owing to the limited data. LIMITATIONS: All included studies were at risk of bias, there was substantial heterogeneity and effects varied considerably across studies. The effect of intervention on autism symptom severity, language development and school placement remains uncertain because of the limited data. The long-term effects are unclear owing to a lack of follow-up data. CONCLUSIONS: This review found limited evidence that early intensive applied behaviour analysis-based interventions may improve cognitive ability and adaptive behaviour, but the long-term impact of the interventions remains unknown. The economic analysis is constrained by the limited effectiveness evidence, but suggests that these interventions are unlikely to be cost-effective unless clear long-term benefits, or a substantial change in which schools children attend, can be identified. FUTURE WORK: Further studies into the effectiveness of early intensive applied behaviour analysis-based interventions may be warranted if they include well-defined, alternative interventions as comparators and collect relevant outcomes. Consideration should be given to future studies that not only address whether or not early intensive applied behaviour analysis-based interventions are clinically effective, but also aim to identify which components of early intensive applied behaviour analysis-based interventions might drive effectiveness. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017068303. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 35. See the NIHR Journals Library website for further project information.

Autism is a lifelong condition that affects how people understand the world and interact with others. Early intensive applied behaviour analysis-based interventions are an approach designed to help young (preschool) autistic children. This approach is often delivered on a one-to-one basis, for 20­50 hours per week, over a period of several years. This project obtained and analysed the original data from studies of early intensive applied behaviour analysis-based interventions, to determine whether or not these interventions are beneficial. It also investigated whether or not the interventions represent good value for money. The results suggest that early intensive applied behaviour analysis-based interventions may improve children's intelligence, communication, social and life skills more than standard approaches. However, some results could be inaccurate or incorrect, and there was no evidence about other important outcomes, such as the severity of autism and where children went to school. Most studies lasted for around 2 years, which means that it is not known if early intensive applied behaviour analysis-based interventions have meaningful long-term benefits. It was not possible to fully assess whether or not these interventions provided value for money, as the benefits of early intensive applied behaviour analysis-based interventions were unclear, although the available evidence suggested that they did not. Early intensive applied behaviour analysis-based interventions may, however, provide value for money if their effects were to last into adulthood, or if receiving early intensive applied behaviour analysis had a large impact on the type of school children attended. Future studies of early interventions may be helpful, but should consider looking at which components of early applied behaviour analysis-based interventions are the most important, rather than at whether or not they work better than other interventions. Future studies should also follow best current research practice and evaluate outcomes that matter to autistic people and their families.

Systematic review and network meta-analysis of the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler in comparison with other long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combinations in COPD.

BACKGROUND: Dual bronchodilation with a long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) fixed-dose combination (FDC) is an established treatment strategy for chronic obstructive pulmonary disease (COPD). The relative efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI 18/9.6 µg) in patients with moderate-to-very severe COPD, compared with other licensed LAMA/LABA FDCs, was investigated using an integrated Bayesian network meta-analysis (NMA). METHODS: A systematic literature review and subsequent screening process identified randomized controlled trials of ⩾10 weeks' duration that enrolled patients aged ⩾40 years with moderate-to-very severe COPD and included at least one LAMA/LABA FDC or open LAMA + LABA treatment arm. NMAs were conducted for outcomes including change from baseline in forced expiratory volume in 1 s (FEV1), St George's Respiratory Questionnaire (SGRQ), and transition dyspnea index (TDI) parameters, annualized rate of exacerbations, use of rescue medication, adverse events, and all-cause withdrawals. Meta-regression and sensitivity analyses accounted for heterogeneity across studies. RESULTS: In total, 29 studies including 34,617 patients contributed to the NMA for efficacy or safety outcomes at week 24 or exacerbations. For all LAMA/LABA FDCs with data available, significantly greater improvements in FEV1 [trough, peak, and area under the curve (AUC)0-4], SGRQ total score and TDI focal score at week 24, and annualized rate of moderate-to-severe exacerbations, were observed versus placebo. Where indirect comparisons were possible, differences between GFF MDI and other LAMA/LABA FDCs were small relative to established margins of clinical relevance, and not statistically significant. The safety and tolerability profile of GFF MDI was consistent with other LAMA/LABA FDCs and placebo. The results of the meta-regression were generally similar to the base case. CONCLUSIONS: GFF MDI demonstrated comparable efficacy and safety outcomes to other LAMA/LABA FDCs. Personalization of treatment choice within the class on the basis of other factors such as patient preference may be appropriate.

Relationship between health-related quality of life and respiratory health status among coal-based sponge iron plant workers in Barjora, India.

BACKGROUND: Many coal-based sponge iron plant workers have poor health-related quality of life in general, and specifically a poor respiratory health status. However, the relationship between their health-related quality of life and respiratory health status is unknown. AIM: This study investigated the relationship between health-related quality of life, measured using the EuroQol-5D (EQ5D), and respiratory health status, measured using the St. George's Respiratory Questionnaire (SGRQ), among coal-based sponge iron plant workers in Barjora, India. METHOD: A cross-sectional study was conducted among coal-based sponge iron plant workers in Barjora, and complete data were available on 252 participants. Spearman's rank correlation coefficients were reported to show the strength of relationship between health-related quality of life and respiratory health status. RESULTS AND CONCLUSION: Significant correlations were found between all EQ5D dimensions/visual analogue scale (VAS) and all SGRQ scores except between EQ5D-VAS and SGRQ-activity. A range of correlations was found. They were moderate between EQ5D-anxiety/depression and SGRQ-symptom, EQ5D-VAS and SGRQ-symptom, and EQ5D-anxiety/depression and SGRQ-total, but weak between all the other factors.

Ustekinumab for Treating Moderately to Severely Active Crohn's Disease after Prior Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited Janssen to submit evidence on the clinical and cost effectiveness of their drug ustekinumab, an interleukin-12/23 inhibitor, for treating moderate-to-severe active Crohn's disease (CD). The Centre for Reviews and Dissemination (CRD) and Centre for Health Economics (CHE) Technology Appraisal Group at the University of York was commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the Company's submission, the ERG's critical review of submitted evidence, and the resulting NICE guidance. The main supporting clinical evidence was derived from four well conducted, randomised controlled trials, comparing ustekinumab with placebo in two sub-populations (conventional care failure and anti-TNFα failure patients) of adults with moderate-to-severe CD. Three trials assessed treatment induction over 8 weeks, while the fourth recruited successfully induced patients into a maintenance trial for 1 year. These trials showed ustekinumab to be more effective than placebo in terms of its ability to induce and maintain clinical response and remission. In the absence of any direct head-to-head data, the Company conducted a network meta-analysis (NMA), which synthesised induction trial data on ustekinumab and relevant comparators (vedolizumab, adalimumab and infliximab) using placebo data as a common comparator. This analysis found ustekinumab to be of comparable efficacy to previously approved biologics in treatment induction. A 'treatment sequence analysis' compared long-term treatment efficacy, finding ustekinumab to be comparable in maintaining treatment response and remission to the three other biologic therapies. However, the ERG had identified many limitations and potential bias in this analysis, and urged caution when interpreting the results. The Company's economic model estimated ustekinumab to be dominant in both sub-populations compared with conventional care; however, the ERG's preferred base-case estimated an incremental cost-effectiveness ratio of £109,279 in the conventional care failure sub-population, and £110,967 in the anti-TNFα failure sub-population when compared with conventional care. However, the ERG identified significant failings in both the model structure and data inputs, which could not be addressed without complete restructuring. The ERG considered that the economic analysis presented by the Company failed to adequately address the decision problem specified in NICE's scope. The NICE Appraisal Committee recommended ustekinumab within its market authorisation, on the grounds of sufficiently similar efficacy and costs to previously recommended biologic therapies. However, the ERG's analyses demonstrated that all currently recommended biologics are unlikely to be cost effective relative to conventional care, raising broader questions regarding the appropriateness of cost-comparison exercises for decision making.

Certolizumab pegol and secukinumab for treating active psoriatic arthritis following inadequate response to disease-modifying antirheumatic drugs: a systematic review and economic evaluation.

BACKGROUND: Several biologic therapies are approved by the National Institute for Health and Care Excellence (NICE) for psoriatic arthritis (PsA) patients who have had an inadequate response to two or more synthetic disease-modifying antirheumatic drugs (DMARDs). NICE does not specifically recommend switching from one biologic to another, and only ustekinumab (UST; STELARA®, Janssen Pharmaceuticals, Inc., Horsham, PA, USA) is recommended after anti-tumour necrosis factor failure. Secukinumab (SEC; COSENTYX®, Novartis International AG, Basel, Switzerland) and certolizumab pegol (CZP; CIMZIA®, UCB Pharma, Brussels, Belgium) have not previously been appraised by NICE. OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of CZP and SEC for treating active PsA in adults in whom DMARDs have been inadequately effective. DESIGN: Systematic review and economic model. DATA SOURCES: Fourteen databases (including MEDLINE and EMBASE) were searched for relevant studies from inception to April 2016 for CZP and SEC studies; update searches were run to identify new comparator studies. REVIEW METHODS: Clinical effectiveness data from randomised controlled trials (RCTs) were synthesised using Bayesian network meta-analysis (NMA) methods to investigate the relative efficacy of SEC and CZP compared with comparator therapies. A de novo model was developed to assess the cost-effectiveness of SEC and CZP compared with the other relevant comparators. The model was specified for three subpopulations, in accordance with the NICE scope (patients who have taken one prior DMARD, patients who have taken two or more prior DMARDs and biologic-experienced patients). The models were further classified according to the level of concomitant psoriasis. RESULTS: Nineteen eligible RCTs were included in the systematic review of short-term efficacy. Most studies were well conducted and were rated as being at low risk of bias. Trials of SEC and CZP demonstrated clinically important efficacy in all key clinical outcomes. At 3 months, patients taking 150 mg of SEC [relative risk (RR) 6.27, 95% confidence interval (CI) 2.55 to 15.43] or CZP (RR 3.29, 95% CI 1.94 to 5.56) were more likely to be responders than patients taking placebo. The NMA results for the biologic-naive subpopulations indicated that the effectiveness of SEC and CZP relative to other biologics and each other was uncertain. Limited data were available for the biologic-experienced subpopulation. Longer-term evidence suggested that these newer biologics reduced disease progression, with the benefits being similar to those seen for older biologics. The de novo model generated incremental cost-effectiveness ratios (ICERs) for three subpopulations and three psoriasis subgroups. In subpopulation 1 (biologic-naive patients who had taken one prior DMARD), CZP was the optimal treatment in the moderate-severe psoriasis subgroup and 150 mg of SEC was optimal in the subgroups of patients with mild-moderate psoriasis or no concomitant psoriasis. In subpopulation 2 (biologic-naive patients who had taken two or more prior DMARDs), etanercept (ETN; ENBREL®, Pfizer Inc., New York City, NY, USA) is likely to be the optimal treatment in all subgroups. The ICERs for SEC and CZP versus best supportive care are in the region of £20,000-30,000 per quality-adjusted life-year (QALY). In subpopulation 3 (biologic-experienced patients or patients in whom biologics are contraindicated), UST is likely to be the optimal treatment (ICERs are in the region of £21,000-27,000 per QALY). The optimal treatment in subpopulation 2 was sensitive to the choice of evidence synthesis model. In subpopulations 2 and 3, results were sensitive to the algorithm for Health Assessment Questionnaire-Disability Index costs. The optimal treatment is not sensitive to the use of biosimilar prices for ETN and infliximab (REMICADE®, Merck Sharp & Dohme, Kenilworth, NJ, USA). CONCLUSIONS: SEC and CZP may be an effective use of NHS resources, depending on the subpopulation and subgroup of psoriasis severity. There are a number of limitations to this assessment, driven mainly by data availability. FUTURE WORK: Trials are needed to inform effectiveness of biologics in biologic-experienced populations. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016033357. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Crizotinib for Untreated Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the National Institute for Health and Care Excellence (NICE) single technology appraisal process, the manufacturer of crizotinib submitted evidence on the clinical and cost effectiveness of crizotinib in untreated anaplastic lymphoma kinase-positive (ALK-positive) non-small-cell lung cancer (NSCLC). Crizotinib has previously been assessed by NICE for patients with previously treated ALK-positive NSCLC (TA 296). It was not approved in this previous appraisal, but had been made available through the cancer drugs fund. As part of this new appraisal, the company included a price discount patient access scheme (PAS). The Centre for Reviews and Dissemination and Centre for Health Economics Technology Appraisal Group at the University of York was commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company's submission and the ERG's review and summarises the resulting NICE guidance issued in August 2016. The main clinical-effectiveness data were derived from a multicentre randomised controlled trial-PROFILE 1014-that compared crizotinib with pemetrexed chemotherapy in combination with carboplatin or cisplatin in patients with untreated non-squamous ALK-positive NSCLC. In the trial, crizotinib demonstrated improvements in progression-free survival (PFS) and overall survival (OS). The company's economic model was a three-state 'area under the curve' Markov model. The base-case incremental cost-effectiveness ratio (ICER) was estimated to be greater than £50,000 per quality-adjusted life-year (QALY) gained (excluding the PAS discount). The ERG assessment of the evidence submitted by the company raised a number of concerns. In terms of the clinical evidence, the OS benefit was highly uncertain due to the cross-over permitted in the trial and the immaturity of the data; only 26% of events had occurred by the data cut-off point. In the economic modelling, the most significant concerns related to the analysis of OS and assumptions made regarding the duration of therapy. The ERG exploratory re-analysis of the OS data relaxed the assumption of proportional hazards made in the company submission, which demonstrated significant uncertainty regarding the OS gains from crizotinib. The ERG reconfigured the economic model so that duration of therapy was based on the area under the curve analysis of the PROFILE 1014 trial, dramatically increasing the cost associated with implementing crizotinib and consequently, substantially increasing the ICER. At the first appraisal meeting, the NICE Appraisal Committee concluded that crizotinib, while clinically effective, was not sufficiently cost effective for use in the UK NHS. Following the consultation, the company offered a revised PAS and conducted extensive re-analysis, resulting in a revised base-case ICER of £47,291 per QALY gained. The NICE Appraisal Committee concluded that crizotinib was likely to be a cost-effective use of NHS resources, despite the uncertainty that persisted around a number of factors, namely the long-term survival benefit of crizotinib. Crizotinib was therefore recommended as an option for untreated ALK-positive advanced NSCLC in adults.

A Review of Ruxolitinib for the Treatment of Myelofibrosis: A Critique of the Evidence.

As part of the National Institute for Health and Care Excellence's (NICE) Single Technology Appraisal (STA) process, ruxolitinib was assessed to determine the clinical and cost effectiveness of its use in the treatment of disease-related splenomegaly or symptoms in adults with myelofibrosis. Ruxolitinib had previously been assessed as part of the STA process and was not recommended in NICE guidance issued in June 2013 (TA289). A review of TA289 was commissioned following the availability of new longer-term survival data; a price discount patient access scheme (PAS) was also introduced. The Centre for Reviews and Dissemination (CRD) and Centre for Health Economics (CHE) Technology Appraisal Group at the University of York was commissioned to act as the independent Evidence Review Group (ERG). This article provides a summary of the manufacturer or sponsor of the technology's (referred to as the company) submission, the ERG review and the resulting NICE guidance issued in March 2016. The main clinical effectiveness data were derived from two good-quality multicentre randomised controlled trials (RCTs): COMFORT-II compared ruxolitinib with best available therapy (BAT) and COMFORT-I compared ruxolitinib with placebo. Both RCTs demonstrated a statistically significant reduction in splenomegaly and its associated symptoms in intermediate-2 and high-risk myelofibrosis patients. Overall survival was statistically significantly improved with ruxolitinib compared with BAT at 3.5 years of follow-up in the COMFORT-II trial (hazard ratio 0.58, 95 % CI 0.36-0.93). Grade 3-4 adverse events were more frequent in the ruxolitinib group than in the BAT group; 42 % compared with 25 %. Evidence relating to patients with lower-risk disease or low platelet counts (50-100 × 109/L) was less robust. The company's economic model was well-presented and had an appropriate model structure. The base-case incremental cost-effectiveness ratio (ICER) was estimated to be around £45,000 per quality-adjusted life-year (QALY) gained (including the PAS discount). Extensive sensitivity and scenario analyses were presented, demonstrating that the estimated ICER was robust to a range of input values and assumptions made in the model. Alternative scenarios presented by the ERG showed only modest increases in the estimated ICER, primarily as a result of including an element of drug wastage within the model. Alternative scenarios resulted in estimated ICERs ranging from around £45,000 to £49,000 per QALY gained (including the PAS discount). At the first appraisal meeting, the NICE Appraisal Committee concluded that ruxolitinib was clinically effective and was a cost effective use of National Health Service (NHS) resources for patients with high-risk myelofibrosis who meet NICE's end-of-life criteria. Following the consultation, the company offered a revised PAS, resulting in a revised base-case ICER of £31,229 per QALY gained. The company also presented new evidence on the cost effectiveness of ruxolitinib in intermediate-2 and high-risk subgroups and a revised version of the model. The NICE Appraisal Committee considered the new evidence and recommended ruxolitinib for the treatment of patients with intermediate-2-risk disease as well as patients with high-risk disease, based on International Prognostic Scoring System (IPSS) prognostic factors.

The healthcare costs of heart failure during the last five years of life: A retrospective cohort study.

BACKGROUND: Evidence on the economic impact of heart failure (HF) is vital in order to predict the cost-effectiveness of novel interventions. We estimate the health system costs of HF during the last five years of life. METHODS: We used linked primary care and mortality data accessed through the Clinical Practice Research Datalink (CPRD) to identify 1555 adults in England who died with HF in 2012/13. We used CPRD and linked Hospital Episode Statistics to estimate the cost of medications, primary and hospital healthcare. Using GLS regression we estimated the relationship between costs, HF diagnosis, proximity to death and patient characteristics. RESULTS: In the last 3months of life, healthcare costs were £8827 (95% CI £8357 to £9296) per patient, more than 90% of which were for inpatient or critical care. In the last 3months, patients spent on average 17.8 (95% CI 16.8 to 18.8) days in hospital and had 8.8 (95% CI 8.4 to 9.1) primary care consultations. Most (931/1555; 59.9%) patients were in hospital on the day of death. Mean quarterly healthcare costs in quarters after HF diagnosis were higher (£1439; [95% CI £1260 to £1619]) than in quarters preceding diagnosis. Older patients and patients with lower comorbidity scores had lower costs. CONCLUSIONS: Healthcare costs increase sharply at the end of life and are dominated by hospital care. There is potential to save money by implementation and evaluation of interventions that are known to reduce hospitalisations for HF, particularly at the end of life.

Symptom lead time distribution in lung cancer: natural history and prospects for early diagnosis.

BACKGROUND: Before their diagnosis, patients with cancer present in primary care more frequently than do matched controls. This has raised hopes that earlier investigation in primary care could lead to earlier stage at diagnosis. METHODS: We re-analysed primary care symptom data collected from 247 lung cancer cases and 1235 matched controls in Devon, UK. We identified the most sensitive and specific definition of symptoms, and estimated its incidence in cases and controls prior to diagnosis. We estimated the symptom lead time (SLT) distribution (the time between symptoms attributable to cancer and diagnosis), taking account of the investigations already carried out in primary care. The impact of route of diagnosis on stage at diagnosis was also examined. RESULTS: Symptom incidence in cases was higher than in controls 2 years before diagnosis, accelerating markedly in the last 6 months. The median SLT was under 3 months, with mean 5.3 months [95% credible interval (CrI) 4.5-6.1] and did not differ by stage at diagnosis. An earlier stage at diagnosis was observed in patients identified through chest X-ray originated in primary care. CONCLUSIONS: Most symptoms preceded clinical diagnosis by only a few months. Symptom-based investigation would lengthen lead times and result in earlier stage at diagnosis in a small proportion of cases, but would be far less effective than standard screening targeted at smokers.

Stratified medicine in European Medicines Agency licensing: a systematic review of predictive biomarkers.

OBJECTIVES: Stratified medicine is often heralded as the future of clinical practice. Key part of stratified medicine is the use of predictive biomarkers, which identify patient subgroups most likely to benefit (or least likely to experience harm) from an intervention. We investigated how many and what predictive biomarkers are currently included in European Medicines Agency (EMA) licensing. SETTING: EMA licensing. PARTICIPANTS: Indications and contraindications of all drugs considered by the EMA and published in 883 European Public Assessment Reports and Pending Decisions. PRIMARY AND SECONDARY OUTCOME MEASURES: Data were collected on: the type of the biomarker, whether it selected a subgroup of patients based on efficacy or toxicity, therapeutic area, marketing status, date of licensing decision, date of inclusion of the biomarker in the indication or contraindication and on orphan designation. RESULTS: 49 biomarker-indication-drug (B-I-D) combinations were identified over 16 years, which included 37 biomarkers and 41 different drugs. All identified biomarkers were molecular. Six drugs (relating to 10 B-I-D combinations) had an orphan designation at the time of licensing. The identified B-I-D combinations were mainly used in cancer and HIV treatment, and also in hepatitis C and three other indications (cystic fibrosis, hyperlipoproteinaemia type I and methemoglobinaemia). In 45 B-I-D combinations, biomarkers were used as predictive of drug efficacy and in four of drug toxicity. It appeared that there was an increase in the number of B-I-D combinations introduced each year; however, the numbers were too small to identify any trends. CONCLUSIONS: Given the large body of literature documenting research into potential predictive biomarkers and extensive investment into stratified medicine, we identified relatively few predictive biomarkers included in licensing. These were also limited to a small number of clinical areas. This might suggest a need for improvement in methods of translation from laboratory findings to clinical practice.

Purification and characterization of a betanidin glucosyltransferase from Amaranthus tricolor L catalyzing non-specific biotransformation of flavonoids.

Betacyanins are the major pigments present in Amaranthus tricolor, a leafy vegetable consumed globally. The terminal glycosylation of the aglycone betanidin is an important step in the biosynthesis of this natural red antioxidant pigment. A betanidin 5-O-glucosyltransferase (BGT) was fully purified to 134 folds (specific activity, 265.2 nkat mg(-1)) from the red amaranth by ammonium sulfate precipitation followed by hydrophobic interaction, anion exchange and size exclusion chromatography. Homogeneity of the purified protein was confirmed by 2-dimensional polyacrylamide gel electrophoresis (2D PAGE). The molecular weight of the enzyme determined by liquid chromatography-mass spectrometry (LC-MS) was found to be 62.8 kDa. Furthermore, the enzyme glycosylated flavonoids (kaempferol and quercetin) but not anthocyanidins, presence of which is mutually exclusive to betacyanin accumulating plants. The apparent Km (344±2.34 µM) and Vmax (17.24 µM min(-1)) of the enzyme were determined by LC-MS/MS. Peptide mass fingerprinting of the purified protein showed 38.4% coverage of peptide masses with anthocyanidin 3-O-glucosyltransferase from Zea mays. Study on this purified enzyme, for the first time, revealed its role of glycosylation in biosynthesis of betacyanin in A. tricolor and indicates promiscuous substrate-specificity.

Total and free testosterone concentrations are strongly influenced by age and central obesity in men with type 1 and type 2 diabetes but correlate weakly with symptoms of androgen deficiency and diabetes-related quality of life.

OBJECTIVE: Testosterone levels are commonly lowered in men with diabetes, but it is unclear how these relate to symptoms of hypogonadism and quality of life. We sought to investigate the relationship between testosterone levels, symptoms of androgen deficiency, erectile function and quality of life in men with type 1 and type 2 diabetes. DESIGN AND SUBJECTS: Cross-sectional study of 115 men with type 2 diabetes, 93 men with type 1 diabetes and 121 healthy controls. MEASUREMENTS: Total, bioavailable and free testosterone levels were measured or calculated by Vermuelen's formula. Quality of life and symptom scores were assessed by the Audit of Diabetes Dependent Quality of Life (ADDQoL), androgen deficiency in the aging male (ADAM) and International Index of Erectile Function (IIEF) questionnaires. RESULTS: Forty-five and sixty-one per cent of men with type 2 diabetes had low total and calculated free testosterone (CFT) levels, respectively. Total testosterone (TT) levels were not lowered in men with type 1 diabetes, but 32% had low CFT. After adjustment for age and waist circumference, only CFT in men with type 2 diabetes (-0·037 nm, 95% CI -0·075 to -0·0003, P = 0.048) remained lowered compared with controls. CFT correlated weakly with ADAM (r = -0·26, 95% CI -0.42 to -0·08, P = 0·006), IIEF (r = 0.19, 95% CI 0.01-0.37, P = 0.042) and ADDQoL (r = 0.21, 95% CI 0·03 to 0·38, P = 0·022) scores in men with type 2, but not type 1 diabetes. Age exerted the predominant effect on erectile function in both groups, in a model incorporating age, testosterone level and complications. CONCLUSIONS: Testosterone levels are strongly affected by age and central obesity in men with type 1 and type 2 diabetes but correlate weakly with symptoms of androgen deficiency and erectile function. Testosterone levels do not appear to be a major determinant of quality of life in patients with diabetes.