Carpal tunnel syndrome and computer exposure at work in two large complementary cohorts.

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A systematic review of the cost-effectiveness of targeted therapies for metastatic non-small cell lung cancer (NSCLC)

Background: Non-small cell lung cancer (NSCLC) imposes a substantial burden on patients, health care systems and society due to increasing incidence and poor survival rates. In recent years, advances in the treatment of metastatic NSCLC have resulted from the introduction of targeted therapies. However, the application of these new agents increases treatment costs considerably. The objective of this article is to review the economic evidence of targeted therapies in metastatic NSCLC. Methods: A systematic literature review was conducted to identify cost-effectiveness (CE) as well as cost-utility studies. Medline, Embase, SciSearch, Cochrane, and 9 other databases were searched from 2000 through April 2013 (including update) for full-text publications. The quality of the studies was assessed via the validated Quality of Health Economic Studies (QHES) instrument. Results: Nineteen studies (including update) involving the MoAb bevacizumab and the Tyrosine-kinase inhibitors erlotinib and gefitinib met all inclusion criteria. The majority of studies analyzed the CE of first-line maintenance and second-line treatment with erlotinib. Five studies dealt with bevacizumab in first-line regimes. Gefitinib and pharmacogenomic profiling were each covered by only two studies. Furthermore, the available evidence was of only fair quality. Conclusion: First-line maintenance treatment with erlotinib compared to Best Supportive Care (BSC) can be considered cost-effective. In comparison to docetaxel, erlotinib is likely to be cost-effective in subsequent treatment regimens as well. The insights for bevacizumab are miscellaneous. There are findings that gefitinib is cost-effective in first- and second-line treatment, however, based on only two studies. The role of pharmacogenomic testing needs to be evaluated. Therefore, future research should improve the available evidence and consider pharmacogenomic profiling as specified by the European Medicines Agency. Upcoming agents like crizotinib and afatinib need to be analyzed as well. © Lange et al.

Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury.

Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited the therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here we developed stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real-time control software that modulate extensor and flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight-bearing capacity, endurance and skilled locomotion in several rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans.

Outcome Prediction of Consciousness Disorders in the Acute Stage Based on a Complementary Motor Behavioural Tool.

INTRODUCTION: Attaining an accurate diagnosis in the acute phase for severely brain-damaged patients presenting Disorders of Consciousness (DOC) is crucial for prognostic validity; such a diagnosis determines further medical management, in terms of therapeutic choices and end-of-life decisions. However, DOC evaluation based on validated scales, such as the Revised Coma Recovery Scale (CRS-R), can lead to an underestimation of consciousness and to frequent misdiagnoses particularly in cases of cognitive motor dissociation due to other aetiologies. The purpose of this study is to determine the clinical signs that lead to a more accurate consciousness assessment allowing more reliable outcome prediction. METHODS: From the Unit of Acute Neurorehabilitation (University Hospital, Lausanne, Switzerland) between 2011 and 2014, we enrolled 33 DOC patients with a DOC diagnosis according to the CRS-R that had been established within 28 days of brain damage. The first CRS-R assessment established the initial diagnosis of Unresponsive Wakefulness Syndrome (UWS) in 20 patients and a Minimally Consciousness State (MCS) in the remaining13 patients. We clinically evaluated the patients over time using the CRS-R scale and concurrently from the beginning with complementary clinical items of a new observational Motor Behaviour Tool (MBT). Primary endpoint was outcome at unit discharge distinguishing two main classes of patients (DOC patients having emerged from DOC and those remaining in DOC) and 6 subclasses detailing the outcome of UWS and MCS patients, respectively. Based on CRS-R and MBT scores assessed separately and jointly, statistical testing was performed in the acute phase using a non-parametric Mann-Whitney U test; longitudinal CRS-R data were modelled with a Generalized Linear Model. RESULTS: Fifty-five per cent of the UWS patients and 77% of the MCS patients had emerged from DOC. First, statistical prediction of the first CRS-R scores did not permit outcome differentiation between classes; longitudinal regression modelling of the CRS-R data identified distinct outcome evolution, but not earlier than 19 days. Second, the MBT yielded a significant outcome predictability in the acute phase (p<0.02, sensitivity>0.81). Third, a statistical comparison of the CRS-R subscales weighted by MBT became significantly predictive for DOC outcome (p<0.02). DISCUSSION: The association of MBT and CRS-R scoring improves significantly the evaluation of consciousness and the predictability of outcome in the acute phase. Subtle motor behaviour assessment provides accurate insight into the amount and the content of consciousness even in the case of cognitive motor dissociation.

Evaluation of the effect of complementary pollination on Actinidia deliciosa 'Hayward' in northwest Portugal

The objective of this research was to study the effect of complementary pollination on kiwifruit production and quality. For 3 years, complementary application of wet or dry pollen have been done at different stages of flower opening on vines in the Portuguese regions of Entre-Douro e Minho and Beira Litoral. Commercial production data were collected and fruit quality attributes were measured at harvest. Complementary pollination did not affect fruit soluble solids content or firmness in any year, and was beneficial for fruit size and commercial production in the third year only, showing that it is important in some conditions, when natural pollination is inadequate.

The Westerly Index as complementary indicator of the North Atlantic oscillation in explaining drought variability across Europe

This paper analyses the influence of different atmospheric circulation indices on the multi-scalar drought variability across Europe by using the Standardized Precipitation Evapotranspiration Index (SPEI). The monthly circulation indices used in this study include the North Atlantic oscillation (NAO), the East Atlantic (EA), the Scandinavian (SCAN) and the East Atlantic-Western Russia (EA-WR) patterns, as well as the recently published Westerly Index (WI), defined as the persistence of westerly winds over the eastern north Atlantic region. The results indicate that European drought variability is better explained by the station-based NAO index and the WI than by any other combination of circulation indices. In northern and central Europe the variability of drought severity for different seasons and time-scales is strongly associated with the WI. On the contrary, the influence of the NAO on southern Europe droughts is stronger than that exerted by the WI. The correlation patterns of the NAO and WI with the SPEI show a spatial complementarity in shaping drought variability across Europe. Lagged correlations of the NAO and WI with the SPEI also indicate enough skill of both indices to anticipate drought severity several months in advance. As long as instrumental series of the NAO and WI are available, their combined use would allow inferring European drought variability for the last two centuries and improve the calibration and interpretation of paleoclimatic proxies associated with drought.

Evaluation of the effect of complementary pollination on Actinidia deliciosa 'Hayward' in northwest Portugal

The objective of this research was to study the effect of complementary pollination on kiwifruit production and quality. For 3 years, complementary application of wet or dry pollen have been done at different stages of flower opening on vines in the Portuguese regions of Entre-Douro e Minho and Beira Litoral. Commercial production data were collected and fruit quality attributes were measured at harvest. Complementary pollination did not affect fruit soluble solids content or firmness in any year, and was beneficial for fruit size and commercial production in the third year only, showing that it is important in some conditions, when natural pollination is inadequate.

Evolution of emerging iPS cell-based therapies for age-related macular degeneration (AMD)

Stem cell-based regenerative medicine is poised to revolutionize the way diseases are treated. In recent years, induced pluripotent stem (iPS) cells, a newly stem cell species, has attracted significant attention. This paper seeks to understand the pathways along which emerging clinical research efforts in the field of iPS cells is evolved. In particular, the empirical case of age-related macular degeneration (AMD) is used, which is the world-pioneering clinical application of iPS cells. In line with the literature, this study explores the interrelations between three different pathways, such as biomedical scientific understanding, development of medical technologies, and learning in clinical practice. For this, a techmining approach is used including co-term, co-citation, and direct citation methods. Scientific publications indexed in the Thomson Reuters' Web of Science and Elsevier's Scopus databases form the basis of the study. This research first explores the iPS cell research landscape through the construction of a co-term map, particularly stressing the location and intensity of disease-tackling efforts; then focus on the evolution of scientific knowledge on AMD through co-citation networks and the main path algorithm on direct citations. At the researcher level, the development of four different research groups working on cell therapies for AMD is evaluated through the software CitNetExplorer. By integrating these approaches, the result shows a wider picture of the complexities inherent in the translation of knowledge into revolutionary clinical methods.

Determinants of the Design and Use of PMS in Portuguese Government Agencies: A Complementary Theoretical Approach

Performance measurement is seen as a main pillar of public management reforms. However, prior research did not mitigate the level of ambiguity on PMS development and use and many questions left unanswered. Our findings provide knowledge on the design and use of PMS in the public sector answer- ing to calls for a complementary approach among institutional and contingency factors. The authors find that the design of PMS and the use of performance information for external purposes are increased to legitimate the organizational’ work and to obtain external support. Moreover, structural variables such as type of agency and management autonomy are also determinants on the organizational responses. Finally, the authors find some coupling between the design of PMS and outcomes. So, both contingent and institutional approaches play an important role on the empirical model.

Using induced pluripotent stem cells (IPSCS) as a replacement for in vivo models to screen novel therapies in chronic myeloid leukaemia (CML)

Tyrpsine kinase inhibitors (TKIs) effectively target progenitors and mature leukaemic cells but prove less effective at eliminating leukaemic stem cells (LSCs) in patients with chronic myeloid leukaemia (CML). Several reports indicate that the TGFβ superfamily pathway is important for LSC survival and quiescence. We conducted extensive microarray analyses to compare expression patterns in normal haemopoietic stem cells (HSC) and progenitors with CML LSC and progenitor populations in chronic phase (CP), accelerated phase (AP) and blast crisis (BC) CML. The BMP/SMAD pathway and downstream signalling molecules were identified as significantly deregulated in all three phases of CML. The changes observed could potentiate altered autocrine signalling, as BMP2, BMP4 (p<0.05), and ACTIVIN A (p<0.001) were all down regulated, whereas BMP7, BMP10 and TGFβ (p<0.05) were up regulated in CP. This was accompanied by up regulation of BMPRI (p<0.05) and downstream SMADs (p<0.005). Interestingly, as CML progressed, the profile altered, with BC patients showing significant over-expression of ACTIVIN A and its receptor ACVR1C. To further characterise the BMP pathway and identify potential candidate biomarkers within a larger cohort, expression analysis of 42 genes in 60 newly diagnosed CP CML patient samples, enrolled on a phase III clinical trial (www.spirit-cml.org) with greater than 12 months follow-up data on their response to TKI was performed. Analysis revealed that the pathway was highly deregulated, with no clear distinction when patients were stratified into good, intermediate and poor response to treatment. One of the major issues in developing new treatments to target LSCs is the ability to test small molecule inhibitors effectively as it is difficult to obtain sufficient LSCs from primary patient material. Using reprogramming technologies, we generated induced pluripotent stem cells (iPSCs) from CP CML patients and normal donors. CML- and normal-derived iPSCs were differentiated along the mesodermal axis to generate haemopoietic and endothelial precursors (haemangioblasts). IPSC-derived haemangioblasts exhibited sensitivity to TKI treatment with increased apoptosis and reduction in the phosphorylation of downstream target proteins. 4 Dual inhibition studies were performed using BMP pathway inhibitors in combination with TKI on CML cell lines, primary cells and patient derived iPSCs. Results indicate that they act synergistically to target CML cells both in the presence and absence of BMP4 ligand. Inhibition resulted in decreased proliferation, irreversible cell cycle arrest, increased apoptosis, reduced haemopoietic colony formation, altered gene expression pattern, reduction in self-renewal and a significant reduction in the phosphorylation of downstream target proteins. These changes offer a therapeutic window in CML, with intervention using BMP inhibitors in combination with TKI having the potential to prevent LSC self-renewal and improve outcome for patients. By successfully developing and validating iPSCs for CML drug screening we hope to substantially reduce the reliance on animal models for early preclinical drug screening in leukaemia.

Long term performance evaluation of small-diameter vascular grafts based on polyvinyl alcohol hydrogel and dextran and MSCs-based therapies using the ovine pre-clinical animal model.

The functional and structural performance of a 5 cm synthetic small diameter vascular graft (SDVG) produced by the copolymerization of polyvinyl alcohol hydrogel with low molecular weight dextran (PVA/Dx graft) associated to mesenchymal stem cells (MSCs)-based therapies and anticoagulant treatment with heparin, clopidogrel and warfarin was tested using the ovine model during the healing period of 24 weeks. The results were compared to the ones obtained with standard expanded polyetetrafluoroethylene grafts (ePTFE graft). Blood flow, vessel and graft diameter measurements, graft appearance and patency rate (PR), thrombus, stenosis and collateral vessel formation were evaluated by B-mode ultrasound, audio and color flow Doppler. Graft and regenerated vessels morphologic evaluation was performed by scanning electronic microscopy (SEM), histopathological and immunohistochemical analysis. All PVA/Dx grafts could maintain a similar or higher PR and systolic / diastolic laminar blood flow velocities were similar to ePTFE grafts. CD14 (macrophages) and α-actin (smooth muscle) staining presented similar results in PVA/Dx/MSCs and ePTFE graft groups. Fibrosis layer was lower and endothelial cells were only detected at graft-artery transitions where it was added the MSCs. In conclusion, PVA/Dx graft can be an excellent scaffold candidate for vascular reconstruction, including clinic mechanically challenging applications, such as SDVGs, especially when associated to MSCs-based therapies to promote higher endothelialization and lower fibrosis of the vascular prosthesis, but also higher PR values.

Bioenergetics of cancer cells in anoxia and role of the miRNAs in melanoma resistance to targeted therapies

Tumours are characterized by a metabolic rewiring that helps transformed cells to survive in harsh conditions. The endogenous inhibitor of the ATP-synthase IF1 is overexpressed in several tumours and it has been proposed to drive metabolic adaptation. In ischemic normal-cells, IF1 acts limiting the ATP consumption by the reverse activity of the ATP-synthase, activated by ΔΨm collapse. Conversely, IF1 role in cancer cells is still unclear. It has been proposed that IF1 favours cancer survival by preventing energy dissipation in low oxygen availability, a frequent condition in solid tumours. Our previous data proved that in cancer cells hypoxia does not abolish ΔΨm, avoiding the ATP-synthase reversal and IF1 activation. In this study, we investigated the bioenergetics of cancer cells in conditions mimicking anoxia to evaluate the possible role of IF1. Data obtained indicate that also in cancer cells the ΔΨm collapse induces the ATP-synthase reversal and its inhibition by IF1. Moreover, we demonstrated that upon uncoupling conditions, IF1 favours cancer cells growth preserving ATP levels and energy charge. We also showed that in these conditions IF1 favours the mitochondrial mass renewal, a mechanism we proposed driving apoptosis-resistance. Cancer adaptability is also associated with the onset of therapy resistance, the major challenge for melanoma treatment. Recent studies demonstrated that miRNAs dysregulation drive melanoma progression and drug-resistance by regulating tumour-suppressor and oncogenes. In this context, we attempted to identify and characterize miRNAs driving resistance to vemurafenib in patient-derived metastatic melanoma cells BRAFV600E-mutated. Our results highlighted that several oncogenic pathways are altered in resistant cells, indicating the complexity of both drug-resistance phenomena and miRNAs action. Profiling analysis identified a group of dysregulated miRNAs conserved in vemurafenib-resistance cells from distinct patients, suggesting that they ubiquitously drive drug-resistance. Functional studies performed with a first miRNA confirmed its pivotal role in resistance towards vemurafenib.

A preclinical study of spinal cord injury focused on cellular and molecular modifications as potential targets for innovative therapies

Spinal Cord Injury (SCI) is a devastating condition for human and animal health. In SCI particularly, neurons, oligodendrocytes precursor cells, and mature oligodendrocytes are highly vulnerable to the toxic microenvironment after the lesion and susceptible to the elevated levels of noxious stimuli. Thus the regenerative response of the organism in case of SCI is significantly reduced, and only little spontaneous amelioration is observed in lesioned patients during the early phases. This work mainly focuses on studying and characterizing the modification induced by the SCI in a preclinical animal model. We investigated the ECM composition in the spinal cord segments surrounding the primary lesion site at a gene expression level. We found Timp1 and CD44 as a crucial hub in the secondary cascade of SCI in both spinal cord segments surrounding the lesion site. Interestingly, a temporal and anatomical difference in gene expression, indicating a complex regulation of ECM genes after SCI that could be used as a tool for regenerative medicine. We also investigated the modification in synaptic plasticity-related gene expression in spinal and supraspinal areas involved in motor control. We confirmed the anatomical and temporal difference in gene expression in spinal cord tissue. This analysis suggests that a molecular mapping of the lesion-induced modification could be a useful tool for regenerative medicine. In the last part, we evaluated the efficacy of an implantable biopolymer loaded with an anti-inflammatory drug and a pro-myelinating agent on the acute phase of SCI in our preclinical model. We found a consistent reduction of the inflammatory state in the spinal lesion site and the cord's surrounding segments. Moreover, we found increased preservation of the spinal cord tissue with a related upregulation of neuronal and oligodendroglial markers after lesion. Our treatment showed effective ameliorating functional outcome and reducing the lesion extension in the chronic phase.

Impaired Incretin Secretion And Pancreatic Dysfunction With Older Age And Diabetes.

To estimate the impact of aging and diabetes on insulin sensitivity, beta-cell function, adipocytokines, and incretin production. Hyperglycemic clamps, arginine tests and meal tolerance tests were performed in 50 non-obese subjects to measure insulin sensitivity (IS) and insulin secretion as well as plasma levels of glucagon, GLP-1 and GIP. Patients with diabetes and healthy control subjects were divided into the following groups: middle-aged type 2 diabetes (MA-DM), aged Type 2 diabetes (A-DM) and middle-aged or aged subjects with normal glucose tolerance (MA-NGT or A-NGT). IS, as determined by the homeostasis model assessment, glucose infusion rate, and oral glucose insulin sensitivity, was reduced in the aged and DM groups compared with MA-NGT, but it was similar in the MA-DM and A-DM groups. Insulinogenic index, first and second phase insulin secretion and the disposition indices, but not insulin response to arginine, were reduced in the aged and DM groups. Postprandial glucagon production was higher in MA-DM compared to MA-NGT. Whereas the GLP-1 production was reduced in A-DM, no differences between groups were observed in GIP production. In non-obese subjects, diabetes and aging impair insulin sensitivity. Insulin production is reduced by aging, and diabetes exacerbates this condition. Aging associated defects superimposed diabetic physiopathology, particularly regarding GLP-1 production. On the other hand, the glucose-independent secretion of insulin was preserved. Knowledge of the complex relationship between aging and diabetes could support the development of physiopathological and pharmacological based therapies.