Multimodal Soft Robotic Actuation and Locomotion.

Diverse and adaptable modes of complex motion observed at different scales in living creatures are challenging to reproduce in robotic systems. Achieving dexterous movement in conventional robots can be difficult due to the many limitations of applying rigid materials. Robots based on soft materials are inherently deformable, compliant, adaptable, and adjustable, making soft robotics conducive to creating machines with complicated actuation and motion gaits. This review examines the mechanisms and modalities of actuation deformation in materials that respond to various stimuli. Then, strategies based on composite materials are considered to build toward actuators that combine multiple actuation modes for sophisticated movements. Examples across literature illustrate the development of soft actuators as free-moving, entirely soft-bodied robots with multiple locomotion gaits via careful manipulation of external stimuli. The review further highlights how the application of soft functional materials into robots with rigid components further enhances their locomotive abilities. Finally, taking advantage of the shape-morphing properties of soft materials, reconfigurable soft robots have shown the capacity for adaptive gaits that enable transition across environments with different locomotive modes for optimal efficiency. Overall, soft materials enable varied multimodal motion in actuators and robots, positioning soft robotics to make real-world applications for intricate and challenging tasks.

Direct-Ink-Writing 3D-Printed Bioelectronics.

The development of wearable and implantable bioelectronics has garnered significant momentum in recent years, driven by the ever-increasing demand for personalized health monitoring, remote patient management, and real-time physiological data collection. The elevated sophistication and advancement of these devices have thus led to the use of many new and unconventional materials which cannot be fulfilled through traditional manufacturing techniques. Three-dimension (3D) printing, also known as additive manufacturing, is an emerging technology that opens new opportunities to fabricate next-generation bioelectronic devices. Some significant advantages include its capacity for material versatility and design freedom, rapid prototyping, and manufacturing efficiency with enhanced capabilities. This review provides an overview of the recent advances in 3D printing of bioelectronics, particularly direct ink writing (DIW), encompassing the methodologies, materials, and applications that have emerged in this rapidly evolving field. This review showcases the broad range of bioelectronic devices fabricated through 3D printing including wearable biophysical sensors, biochemical sensors, electrophysiological sensors, energy devices, multimodal systems, implantable devices, and soft robots. This review will also discuss the advantages, existing challenges, and outlook of applying DIW 3D printing for the development of bioelectronic devices toward healthcare applications.

Anisotropic Ion Conducting Particulate Composites for Bioelectronics.

Acquisition, processing, and manipulation of biological signals require transistor circuits capable of ion to electron conversion. However, use of this class of transistors in integrated sensors or circuits is limited due to difficulty in patterning biocompatible electrolytes for independent operation of transistors. It is hypothesized that it would be possible to eliminate the need for electrolyte patterning by enabling directional ion conduction as a property of the material serving as electrolyte. Here, the anisotropic ion conductor (AIC) is developed as a soft, biocompatible composite material comprised of ion-conducting particles and an insulating polymer. AIC displays strongly anisotropic ion conduction with vertical conduction comparable to isotropic electrolytes over extended time periods. AIC allows effective hydration of conducting polymers to establish volumetric capacitance, which is critical for the operation of electrochemical transistors. AIC enables dense patterning of transistors with minimal leakage using simple solution-based deposition techniques. Lastly, AIC can be utilized as a dry, anisotropic interface with human skin that is capable of non-invasive acquisition of individual motor action potentials. The properties of AIC position it to enable implementation of a wide range of large-scale organic bioelectronics and enhance their translation to human health applications.

Cage Environment Regulates Gut Microbiota Independent of Toll-Like Receptors.

The gut microbiome orchestrates epithelial homeostasis and both local and remote immunological responses. Critical to these regulatory interactions are innate immune receptors termed Toll-like receptors (TLRs). Studies to date have implicated innate immunity and Toll-like receptors in shaping key features of the gut microbiome. However, a variety of biological and environmental variables are also implicated in determining gut microbiota composition. In this report, we hypothesized that cohousing and environment dominated the regulation of the gut microbiota in animal models independent of innate immunity. To determine the importance of these variables, innate immunity, or environment in shaping gut microbiota, we used a randomized cohousing strategy and transgenic TLR-deficient mice. We have found that mice cohoused together by genotype exhibited limited changes over time in the composition of the gut microbiota. However, for mice randomized to cage, we report extensive changes in the gut microbiota, independent of TLR function, whereby the fecal microbiota of TLR-deficient mice converges with that of wild-type mice. TLR5-deficient mice in these experiments exhibit greater susceptibility to comparative changes in the microbiota than other TLR-deficient mice and wild-type mice. Our work has broad implications for the study of innate immunity and host-microbiota interactions. Given the profound impact that gut dysbiosis may have on immunity, this report highlights the potential impact of cohousing on the gut microbiota and indices of inflammation as outcomes in biological models of infectious or inflammatory disease.

Decision-making by the NICE Interventional Procedures Advisory Committee.

BACKGROUND: This study explored the evidence base for recommendations by the National Institute of Health and Care Excellence (NICE) Interventional Procedures Advisory Committee, the only NICE committee not to consider cost. The four potential recommendations are: Standard Arrangements (can be performed as routine practice in the NHS); Special Arrangements (can be done under certain conditions); Research Only; and Do Not Do. METHODS: Quantitative content analysis of data extracted from all published Interventional Procedure Guidance (IPG) for 2003-2018 (n = 496) was undertaken. All data were extracted independently by two researchers; disagreements were clarified by consensus. Data were tabulated, descriptive statistics produced, and regression analyses performed. RESULTS: The proportion of IPGs by recommendation was: 50·0 per cent Standard Arrangements; 37·2 per cent Special Arrangements; 11·1 per cent Research Only; and 1·6 per cent Do Not Do. There was a clear trend over time: the proportion of recommendations for Standard Arrangements decreased, whereas the evidence threshold increased. Adjusted mean numbers of patients in the evidence base by recommendation type were: Standard, 4867; Special, 709; Research Only, 386. Regression analyses confirmed that the year of recommendation, numbers of patients and levels of evidence all affected the likely recommendation. CONCLUSION: This study suggests that the likelihood of achieving the most positive recommendation (Standard Arrangements) is decreasing, and that this is most likely due to evidential requirements becoming more demanding. These findings are distinct from those reported for other NICE committees, for which the cost and statistical superiority of new therapies are among the drivers of recommendations.

ANTECEDENTES: Este estudio analiza los niveles de evidencia de las recomendaciones propuestas por el Interventional Procedures Advisory Committee del National Institute of Health and Care Excellence (NICE), el único comité NICE que no tiene en consideración los costes en la guía para los procedimientos de intervención. Las cuatro recomendaciones potenciales son: disposiciones estándar (se pueden efectuar sin restricciones en el marco del NHS); disposiciones especiales (se pueden efectuar bajo ciertas condiciones), en el ámbito de la investigación solo; y no intervenir. MÉTODOS: Se realizó un análisis cuantitativo del contenido de todas las Interventional Procedure Guidance (IPG) publicadas entre 2003-2018 (n = 496). Se obtuvieron todos los datos de forma independiente por dos investigadores y los desacuerdos entre ellos se decidieron por consenso. Se tabularon los datos y se realizaron estadísticas descriptivas y análisis de regresión. RESULTADOS: La proporción de las IPG según el tipo de recomendación eran estándar en el 50% de los casos, especial en el 37%, solo investigación en el 11% y no intervenir en el 2%. Se observó una clara tendencia a lo largo del tiempo: la proporción de recomendaciones del tipo de disposiciones estándar disminuía, mientras que el umbral para la evidencia aumentaba. La media ajustada del número de pacientes para cada tipo de recomendación (estándar, específica y solo investigación) fue de 4.867, 709 y 386, respectivamente. Los análisis de regresión confirmaron que el año de la recomendación, el número de pacientes y los niveles de evidencia afectaban el tipo de recomendación. Estos resultados son diferentes a los relativos a otros comités de NICE, en los que el coste y la superioridad estadística de las nuevas terapias son los motores de las recomendaciones. CONCLUSIÓN: Este estudio sugiere que la probabilidad de lograr la recomendación más positiva (disposición estándar) está disminuyendo, y ello con toda probabilidad es debido a que los requerimientos relacionados con la evidencia son cada vez más exigentes.

Pathophysiological role of respiratory dysbiosis in hospital-acquired pneumonia.

Hospital-acquired pneumonia is a major cause of morbidity and mortality. The incidence of hospital-acquired pneumonia remains high globally and treatment can often be ineffective. Here, we review the available data and unanswered questions surrounding hospital-acquired pneumonia, discuss alterations of the respiratory microbiome and of the mucosal immunity in patients admitted to hospital, and explore potential approaches to stratify patients for tailored treatments. The lungs have been considered a sterile organ for decades because microbiological culture techniques had shown negative results. Culture-independent techniques have shown that healthy lungs harbour a diverse and dynamic ecosystem of bacteria, changing our comprehension of respiratory physiopathology. Understanding dysbiosis of the respiratory microbiome and altered mucosal immunity in patients with critical illness holds great promise to develop targeted host-directed immunotherapy to reduce ineffective treatment, to improve patient outcomes, and to tackle the global threat of resistant bacteria that cause these infections.

Human leucocyte antigen-adverse drug reaction associations: from a perspective of ethnicity.

Whilst immune-mediated adverse drug reactions (ADRs) are rare, they are potentially life-threatening and present a major problem for clinicians. The underlying mechanisms that cause ADRs are not fully understood although genomewide association studies (GWAS) and case-control investigations have associated human leucocyte antigen (HLA) alleles as risk factors. There is evidence that a patient's ethnic background can have an impact on their risk of developing an ADR. This review summarizes the evidence related to HLA alleles and ADRs with particular focus on patient ethnicity. Our analysis indicated that many of the alleles which have been associated with ADRs are found at higher frequencies in Asian populations. The data also showed that many of the alleles that are reported to be statistically significantly associated with ADRs are in linkage disequilibrium with each other and that they form haplotypes specific to certain ethnicities indicating at least some of the allele associations may not be causal.

The respiratory tract microbiome and lung inflammation: a two-way street.

The lungs are not sterile or free from bacteria; rather, they harbor a distinct microbiome whose composition is driven by different ecological rules than for the gastrointestinal tract. During disease, there is often a shift in community composition towards Gammaproteobacteria, the bacterial class that contains many common lung-associated gram-negative "pathogens." Numerous byproducts of host inflammation are growth factors for these bacteria. The extracellular nutrient supply for bacteria in the lungs, which is severely limited during health, markedly increases due to the presence of mucus and vascular permeability. While Gammaproteobacteria benefit from airway inflammation, they also encode molecular components that promote inflammation, potentially creating a cyclical inflammatory mechanism. In contrast, Prevotella species that are routinely acquired via microaspiration from the oral cavity may participate in immunologic homeostasis of the airways.vAreas of future research include determining for specific lung diseases (1) whether an altered lung microbiome initiates disease pathogenesis, promotes chronic inflammation, or is merely a marker of injury and inflammation, (2) whether the lung microbiome can be manipulated therapeutically to change disease progression, (3) what molecules (metabolites) generated during an inflammatory response promote cross-kingdom signaling, and (4) how the lung "ecosystem" collapses during pneumonia, to be dominated by a single pathogen.

Standards of care in cauda equina syndrome.

What constitutes cauda equina syndrome (CES), how it should be subclassified and how urgently to image and operate on patients with CES are all matters of debate. A structured review of the literature has led us to evaluate the science and to propose evidence-based guidelines for the management of CES. Our conclusions include this guidance: pain only; MRI negative - recommend: analgesia, ensure imaging complete (not just lumbar spine) adequate follow-up. Bilateral radiculopathy (CESS) with a large central disc prolapse - recommend: discuss with the patient and if for surgery, the next day (unless deteriorates to CESI in which case emergency surgery); CESI - recommend: the true emergency for surgery by day or night; a large central PLID with uncertainty as to whether CESI or CESR (e.g. catheterised prior to CESR) or where there is residual cauda equina nerve root function or early CESR - recommend: treat as an emergency by day or night. Where there has been prolonged CESR and/or no residual sacral nerve root function - recommend: treat on the following day's list.

Safety and efficacy of pharmacological thromboprophylaxis for hospitalized patients with cirrhosis: a single-center retrospective cohort study.

BACKGROUND: Hospitalized patients with cirrhosis are at increased risk for venous thromboembolism (VTE). The benefits and risks of pharmacological thromboprohylaxis in these patients have not been well studied. OBJECTIVES: To examine the safety and efficacy of pharmacological VTE prophylaxis in hospitalized cirrhotic patients. PATIENTS/METHODS: Retrospective cohort study of patients with cirrhosis hospitalized at an academic tertiary care referral center over a 5-year period. RESULTS: Six hundred hospital admissions accounting for 402 patients were included. VTE prophylaxis was administered during 296 (49%) admissions. Patients receiving VTE prophylaxis were older (59 years vs. 55 years, P < 0.001), had longer lengths of stay (9.6 days vs. 6.8 days, P = 0.002), and lower Model for End-Stage Liver Disease scores (13.2 vs. 16.1, P < 0.001). In-hospital bleeding events (8.1% vs. 5.5%, P = 0.258), gastrointestinal bleeding events (3.0% vs. 3.2% P = 0.52), new VTE events (2.37% vs. 1.65%, P = 0.537), and mortality (8.4% vs. 7.3%, P = 0.599) were similar in the two groups. VTE prophylaxis did not reduce the risk of VTE (odds ratio 0.94, 95% confidence interval 0.23-3.71), and patients receiving unfractionated heparin, but not low molecular weight heparin, were at increased risk for in-hospital bleeding events (odds ratio 2.38, 95% confidence interval 1.15-4.94 vs. 0.87, 0.37-2.05, respectively). CONCLUSION: The rate of VTE in this cohort of hospitalized cirrhotic patients was low and was unaffected by pharmacological thromboprophylaxis. Unfractionated heparin was associated with an increased risk for in-hospital bleeding, suggesting that if thromboprophylaxis is indicated, low molecular weight heparin may be favored.

Exploring the influence of trust relationships on motivation in the health sector: a systematic review.

BACKGROUND: Dedicated and motivated health workers (HWs) play a major role in delivering efficient and effective health services that improve patients' experience of health care. Growing interest in HW motivation has led to a global focus on pay for performance strategies, but less attention has been paid to nurturing intrinsic motivation. Workplace trust relationships involve fair treatment and respectful interactions between individuals. Such relationships enable cooperation among HWs and their colleagues, supervisors, managers and patients and may act as a source of intrinsic motivation. This paper presents findings from a qualitative systematic review of empirical studies providing evidence on HW motivation, to consider what these studies suggest about the possible influence of workplace trust relationships over motivation. METHODS: Five electronic databases were searched for articles reporting research findings about HW motivation for various cadres published in the 10-year period 2003 to 2013 and with available full free text in the English language. Data extraction involved consideration of the links between trust relationships and motivation, by identifying how studies directly or indirectly mention and discuss relevant factors. RESULTS: Twenty-three articles from low- and middle-income countries and eight from high-income countries that met predetermined quality and inclusion criteria were appraised and subjected to thematic synthesis. Workplace trust relationships with colleagues, supervisors and managers, employing organisation and patients directly and indirectly influence HW motivation. Motivational factors identified as linked to trust include respect; recognition, appreciation and rewards; supervision; teamwork; management support; autonomy; communication, feedback and openness; and staff shortages and resource inadequacy. CONCLUSION: To the authors' knowledge, this is the first systematic review on trust and motivation in the health sector. Evidence indicates that workplace trust relationships encourage social interactions and cooperation among HWs, have impact on the intrinsic motivation of HWs and have consequences for retention, performance and quality of care. Human resource management and organisational practices are critical in sustaining workplace trust and HW motivation. Research and assessment of the levels of motivation and factors that encourage workplace trust relationships should include how trust and motivation interact and operate for retention, performance and quality of care.

Chemical constituents from Gouania longipetala and Glyphaea brevis.

Five compounds were isolated altogether from the two medicinal plants. Glycerol monotricosanoate (1), palmarumycin BG1 (2) and de-O-methyllasiodiplodin (3) were isolated from Gouania longipetala. In addition, epicatechin (4) and its dimer procyanidin B2 (5) were isolated from the stem bark of Glyphaea brevis. Their structures were elucidated by using spectroscopic experiments. They exhibited radical scavenging and moderate antibacterial effects.

Assessing variation in the costs of care among patients awaiting liver transplantation.

Previous economic analyses of liver transplantation have focused on the cost of the transplant and subsequent care. Accurate characterization of the pretransplant costs, indexed to severity of illness, is needed to assess the economic burden of liver disease. A novel data set linking Medicare claims with transplant registry data for 15,710 liver transplant recipients was used to determine average monthly waitlist spending (N = 249,434 waitlist months) using multivariable linear regression models to adjust for recipient characteristics including Model for End-Stage Liver Disease (MELD) score. Characteristics associated with higher spending included older age, female gender, hepatocellular carcinoma, diabetes, hypertension and increasing MELD score (p < 0.05 for all). Spending increased exponentially with severity of illness: expected monthly spending at a MELD score of 30 was 10 times higher than at MELD of 20 ($22,685 vs. $2030). Monthly spending within MELD strata also varied geographically. For candidates with a MELD score of 35, spending varied from $19,548 (region 10) to $36,099 (region 7). Regional variation in waitlist costs may reflect the impact of longer waiting times on greater pretransplant hospitalization rates among high MELD score patients. Reducing the number of high MELD waitlist patients through improved medical management and novel organ allocation systems could decrease total spending for end-stage liver care.

Community-based distribution of misoprostol to prevent postpartum haemorrhage at home births: results from operations research in rural Ghana.

OBJECTIVE: To report on a rigorous distribution and monitoring plan to track misoprostol for community-based distribution to reduce postpartum haemorrhage (PPH) in rural Ghana. DESIGN: Operations research. SETTING: Rural Ghana. SAMPLE: Women in third trimester of pregnancy presenting to primary health centres (PHCs) for antenatal care (ANC). METHODS: Ghana Health Service (GHS), Millennium Village Projects, and the University of Illinois at Chicago conducted an operations research study designed to assess the safety, feasibility, and acceptability of community-based distribution of misoprostol to prevent PPH at home deliveries in rural Ghana. One thousand doses (3000 tablets, 200 µg each) were obtained from the Family Health Division of GHS. Three 200-µg tablets of misoprostol (600 µg) in foil packets were packaged together in secured transparent plastic packets labelled with pictorial messages and distributed to midwives at seven PHCs for distribution to pregnant women. MAIN OUTCOME MEASURES: Correct use of misoprostol in home deliveries and retrieval of unused misoprostol doses, PPH rates and maternal mortality. RESULTS: Of the 999 doses distributed to midwives, 982 (98.3%) were successfully tracked, with a 1.7% lost to follow-up rate. Midwives distributed 654 doses to women at third-trimester ANC visits. Of women who had misoprostol to use at home, 81% had an institutional delivery and were able to return the misoprostol safely to the midwife. Of the women that used misoprostol, 99% used the misoprostol correctly. CONCLUSIONS: This study clearly demonstrates that misoprostol distributed antenatally to pregnant women can be used accurately and reliably by rural Ghanaian women, and should be considered for policy implementation across Ghana and other countries with high home birth rates and maternal mortality ratios.

A systematic review of risk assessment strategies for populations at high risk of engaging in violent behaviour: update 2002-8.

BACKGROUND: This review systematically examines the research literature published in the period 2002-8 on structured violence risk assessment instruments designed for use in mental health services or the criminal justice system. It adopted much broader inclusion criteria than previous reviews in the same area in order to capture and summarise data on the widest possible range of available instruments. OBJECTIVES: To address two questions: (1) what study characteristics are associated with a risk assessment instrument score being significantly associated with a violent outcome? and (2) which risk assessment instruments have the highest level of predictive validity for a violent outcome? DATA SOURCES: Nineteen bibliographic databases were searched from January 2002 to April 2008, including PsycINFO, MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, British Nursing Index, International Bibliography of the Social Sciences, Education Resources Information Centre, The Cochrane Library and Web of Knowledge. REVIEW METHODS: Inclusion criteria for studies were (1) evaluation of a structured risk tool; (2) outcome measure of interpersonal violence; (3) participants aged 17 years or over; and (4) participants with a mental disorder and/or at least one offence and/or at least one indictable offence. A series of bivariate analyses using either a chi-squared test or Spearman's rank-order correlation were conducted to explore associations between study characteristics and outcomes. Data from a subset of studies reporting area under the curve (AUC) analysis were combined to provide estimates of mean validity. RESULTS: For the overall set of included studies (n = 959), over three-quarters (77%) were conducted in the USA, Canada or the UK. Two-thirds of all studies were conducted with offenders who had either no formal mental health diagnosis (43%) or forensic samples with a formal diagnosis (25%). The Psychopathy Checklist-Revised was tested in the largest number of studies (n = 192). Most studies (78%) reported a statistically significant (p < 0.05) relationship between the instrument score and a violent outcome. Prospective data collection (chi-squared = 4.4, p = 0.035), number of people recruited (U = 27.8, p = 0.012) and number of participants at end point (U = 26.9, p = 0.04) were significantly associated with predictive validity. For those instruments tested in five or more studies reporting AUC values, the General Statistical Information on Recidivism instrument had the highest mean AUC (0.73). LIMITATIONS: Agreement between pairs of reviewers in the initial pilot exercises was good but less than perfect, so discrepancies may be present given the complexity and subjectivity of some aspects of violence research. Only five of the seven calendar years (2003-7) are completely covered, with partial coverage of 2002 and 2008. There is no weighting for sample or effect sizes when results from studies are aggregated. CONCLUSIONS: A very large number of studies examining the relationship between a structured instrument and a violent outcome were published in this relatively short 7-year period. The general quality of the literature is weak in places (e.g. over-reliance on cross-sectional designs) and a vast range of distinct instruments have been tested to varying degrees. However, there is evidence of some convergence around a small number of high-performing instruments and identification of the components of a high-quality evaluation approach, including AUC analysis. The upper limits (AUC ≥ 0.85) of instrument-based prediction have probably been achieved and are unlikely to be exceeded using instruments alone. FUNDING: The National Institute for Health Research Health Technology Assessment and Research for Patient Benefit programmes.

Clinical effectiveness and cost-effectiveness of first-line chemotherapy for adult patients with locally advanced or metastatic non-small cell lung cancer: a systematic review and economic evaluation.

BACKGROUND: The National Institute for Health and Care Excellence (NICE) has issued multiple guidance for the first-line management of patients with lung cancer and recommends different combinations of chemotherapy treatments. This review provides a synthesis of clinical effectiveness and cost-effectiveness evidence supporting current guidance. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of first-line chemotherapy currently licensed in Europe and recommended by NICE, for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). DATA SOURCES: Three electronic databases (MEDLINE, EMBASE and The Cochrane Library) were searched from 2001 to August 2010. REVIEW METHODS: Trials that compared first-line chemotherapy currently licensed in Europe and recommended by NICE in chemotherapy-naive adult patients with locally advanced or metastatic NSCLC were included. Data on key outcomes including, but not limited to, overall survival (OS), progression-free survival (PFS) and adverse events (AEs) were extracted. For the assessment of cost-effectiveness, outcomes included incremental cost per quality-adjusted life-year (QALY) gained. Analyses were performed for three NSCLC subpopulations: patients with predominantly squamous disease, patients with predominantly non-squamous disease and patients with epidermal growth factor receptor (EGFR) mutation-positive (M+) status. Meta-analysis and mixed-treatment comparison methodology were conducted where appropriate. RESULTS: Twenty-three trials involving > 11,000 patients in total met the inclusion criteria. The quality of the trials was poor. In the case of patients with squamous disease, there were no statistically significant differences in OS between treatment regimes. The mixed-treatment comparison demonstrated that, in patients with non-squamous disease, pemetrexed (Alimta®, Eli Lilly and Company; PEM) + platinum (PLAT) increases OS statistically significantly compared with gemcitabine (Gemzar®, Eli Lilly and Company; GEM) + PLAT [hazard ratio (HR) = 0.85; 95% confidence interval (CI) 0.74 to 0.98] and that paclitaxel (Abraxane®, Celgene Corporation; PAX) + PLAT increases OS statistically significantly compared with docetaxel (Taxotere®, Sanofi-aventis; DOC) + PLAT (HR = 0.79, 95% CI 0.66 to 0.93). None of the comparisons found any statistically significant differences in OS among patients with EGFR M+ status. Direct meta-analysis showed a statistically significant improvement in PFS with gefitinib (Iressa®, AstraZeneca; GEF) compared with DOC + PLAT and PAX + PLAT (HR = 0.49; 95% CI 0.33 to 0.73; and HR = 0.38; 95% CI 0.24 to 0.60, respectively). No papers related to UK decision-making were identified. A de novo economic model was developed. Using list prices (British National Formulary), cisplatin (CIS) doublets are preferable to carboplatin doublets, but this is reversed if electronic market information tool prices are used, in which case drug administration costs then become more important than drug acquisition costs. For patients with both squamous and non-squamous disease, moving from low to moderate willingness-to-pay thresholds, the preferred drugs are PAX → GEM → DOC. However, in patients with non-squamous disease, PEM + CIS resulted in increased OS and would be considered cost-effective up to £35,000 per QALY gained. For patients with EGFR M+, use of GEF compared with PAX or DOC yields very high incremental cost-effectiveness ratios. Vinorelbine (Navelbine®, Pierre Fabre Pharmaceutical Inc.) was not shown to be cost-effective in any comparison. LIMITATIONS: Poor trial quality and a lack of evidence for all drug comparisons complicated and limited the data analysis. Outcomes and adverse effects are not consistently combined across the trials. Few trials reported quality-of-life data despite their relevance to patients and clinicians. CONCLUSIONS: The results of this comprehensive review are unique to NSCLC and will assist clinicians to make decisions regarding the treatment of patients with advanced NSCLC. The design of future lung cancer trials needs to reflect the influence of factors such as histology, genetics and the new prognostic biomarkers that are currently being identified. In addition, trials will need to be adequately powered so as to be able to test for statistically significant clinical effectiveness differences within patient populations. New initiatives are in place to record detailed information on the precise chemotherapy (and targeted chemotherapy) regimens being used, together with data on age, cell type, stage of disease and performance status, allowing for very detailed observational audits of management and outcomes at a population level. It would be useful if these initiatives could be expanded to include the collection of health economics data. FUNDING: The National Institute for Health Research Health Technology Assessment.

Clinical effectiveness of first-line chemoradiation for adult patients with locally advanced non-small cell lung cancer: a systematic review.

BACKGROUND: The National Institute for Health and Clinical Excellence has issued guidelines on the treatment of non-small cell lung cancer (NSCLC) and recommends that patients with stage IIIA-IIIB disease who are not amenable to surgery be treated with potentially curative chemoradiation (CTX-RT). This review was conducted as part of a larger systematic review of all first-line chemotherapy (CTX) and CTX-RT treatments for patients with locally advanced or metastatic NSCLC. However, it was considered that patients with potentially curable disease (e.g. stage IIIA) are different from those with advanced disease, who are suitable for palliative treatment only, and therefore the results should be reported separately. OBJECTIVE: To evaluate the clinical effectiveness of first-line CTX in addition to radiotherapy (RT) (CTX-RT vs CTX-RT) for adult patients with locally advanced NSCLC who are suitable for potentially curative treatment. DATA SOURCES: Three electronic databases (MEDLINE, EMBASE and The Cochrane Library) were searched from January 1990 to September 2010. REVIEW METHODS: Inclusion criteria comprised adult patients with locally advanced NSCLC, trials that compared any first-line CTX-RT therapy (induction, sequential, concurrent and consolidation) and outcomes of overall survival (OS) and/or progression-free survival (PFS). The results of clinical data extraction and quality assessment were summarised in tables and with narrative description. Direct meta-analyses using OS data were undertaken where possible: sequential CTX-RT compared with concurrent CTX-RT; sequential CTX-RT compared with concurrent/consolidation CTX-RT; and sequential CTX-RT compared with concurrent CTX-RT with or without consolidation. There were not sufficient data to perform meta-analysis on PFS. RESULTS: Of the 240 potentially relevant studies that were published post 2000, 19 met the inclusion criteria and compared CTX-RT with CTX-RT. The results from the OS meta-analysis comparing sequential CTX-RT with concurrent CTX-RT appear to show an OS advantage for concurrent CTX-RT arms over sequential arms; this result is not statistically significant [hazard ratio (HR) 0.79; 95% confidence interval (CI) 0.50 to 1.25)]. The results from the OS meta-analysis comparing sequential CTX-RT with concurrent/consolidation CTX-RT appear to show a statistically significant OS advantage for concurrent/consolidation CTX-RT treatment over sequential treatment (HR 0.68; 95% CI 0.55 to 0.83). The results from the OS meta-analysis comparing sequential CTX-RT with concurrent CTX-RT with or without consolidation appear to show a statistically significant OS advantage for concurrent CTX-RT with or without consolidation over sequential treatment (HR 0.72; 95% CI 0.61 to 0.84). LIMITATIONS: This report provides a summary and critical appraisal of a comprehensive evidence base of CTX-RT trials; however, it is possible that additional trials have been reported since our last literature search. It is disappointing that the quality of the research in this area does not meet the accepted quality standards regarding trial design and reporting. CONCLUSIONS: This review identified that the research conducted in the area of CTX-RT was generally of poor quality and suffered from a lack of reporting of all important clinical findings, including OS. The 19 trials included in the systematic review were too disparate to form any conclusions as to the effectiveness of individual CTX agents or types of RT. The focus of primary research should be good methodological quality; appropriate allocation of concealment and randomisation, and comprehensive reporting of key outcomes, will enable meaningful synthesis and conclusions to be drawn. FUNDING: The National Institute for Health Research Health Technology Assessment programme.