Nutritional risk screening (NRS 2002): a new method based on an analysis of controlled clinical trials

A system for screening of nutritional risk is described. It is based on the concept that nutritional support is indicated in patients who are severely ill with increased nutritional requirements, or who are severely undernourished, or who have certain degrees of severity of disease in combination with certain degrees of undernutrition. Degrees of severity of disease and undernutrition were defined as absent, mild, moderate or severe from data sets in a selected number of randomized controlled trials (RCTs) and converted to a numeric score. After completion, the screening system was validated against all published RCTs known to us of nutritional support vs spontaneous intake to investigate whether the screening system could distinguish between trials with a positive outcome and trials with no effect on outcome.

In vivo bisphenol-a release from dental pit and fissure sealants: a systematic review

OBJECTIVE To search the literature and assess the short- and long-term release of bisphenol-A (BPA) in human tissues after treatment with dental sealants. DATA Two review authors performed data extraction independently and in duplicate using data collection forms. Disagreements were resolved by discussion with an arbiter. SOURCES Electronic database searches of published and unpublished literature were performed. The following electronic databases with no language and publication date restrictions were searched: MEDLINE (via Ovid and Pubmed), EMBASE (via ovid), Cochrane Trials Register and CENTRAL. The reference lists of all eligible studies were hand-searched. STUDY SELECTION In the absence of RCTs, six interventional and two observational studies, examining in vivo BPA release in human salivary, blood and urinary samples, were included. Due to the heterogeneity in methodology and reporting, the main synthesis of the results was qualitative. The quantitative synthesis based on the weighted Z-test could only include two studies. BPA levels identified in saliva ranged from traces below the method's detection limit to 30 μg/ml. In urine, BPA quantities spanned from 0.17 mg/g to 45.4 mg/g. BPA was not traced in any blood sample at any point of time in the relevant studies. The quantitative analysis showed evidence of BPA release one hour after sealant placement compared to the amount traced before restoration (Stouffer's z trend: <0.001). CONCLUSIONS The available evidence on this topic derived from studies that represent a moderate level of evidence. Nevertheless, the available evidence supports that BPA is released in saliva after sealant placement. CLINICAL SIGNIFICANCE From the qualititative and quantitative synthesis of studies, it is reasonable to conclude that BPA is released after placement of some dental pit and fissure sealants in the oral cavity. The biggest quantities are detected in saliva immediately after or one hour after their placement.

Bisphenol-A and residual monomer leaching from orthodontic adhesive resins and polycarbonate brackets: a systematic review

INTRODUCTION The objective of this systematic review was to assess the short- and long-term release of components of orthodontic adhesives and polycarbonate brackets in the oral environment. METHODS Electronic database searches of published and unpublished literature were performed. The following electronic databases with no language and publication date restrictions were searched: MEDLINE (via Ovid and PubMed), EMBASE (via Ovid), Cochrane Oral Health Group's Trials Register, and CENTRAL. Unpublished literature was searched on ClinicalTrials.gov, the National Research Register, and Pro-Quest Dissertation Abstracts and Thesis database. The reference lists of all eligible studies were checked for additional studies. Two review authors performed data extraction independently and in duplicate using data collection forms. Disagreements were resolved by discussion or the involvement of an arbiter. RESULTS No randomized controlled trial was identified. In the absence of randomized controlled trials, observational studies were included. Eleven studies met the inclusion criteria. All were observational studies conducted in vivo or in vitro. The bisphenol-A release from orthodontic bonding resins was found to be between 0.85 and 20.88 ng per milliliter in vivo, and from traces to 65.67 ppm in vitro. Polycarbonate brackets released amounts of 22.24 μg per gram in ethanol solution and 697 μg per gram after 40 months in water. Bis-GMA and TEGDMA leaching in vitro reached levels of 64 and 174 mg per 10 μL, respectively. Because of the heterogeneity in methodologies and reporting, only qualitative synthesis was performed. CONCLUSIONS The available evidence on this topic derived from observational in-vivo and in-vitro studies that represent a moderate level of evidence. The variety of setups and the different units allied to the diversity of reporting among studies did not allow calculation of pooled estimates.

The effectiveness of laceback ligatures during initial orthodontic alignment: a systematic review and meta-analysis

Lacebacks may be used to limit unwanted incisor proclination during initial orthodontic alignment; however, their use has not met with universal approval. This systematic review aims to appraise the evidence in relation to the effectiveness of lacebacks in controlling incisor position during initial alignment. Electronic database searches of published literature (MEDLINE via Ovid, Cochrane Central Register of Controlled Trials, LILACS, and IBECS) and unpublished literature were performed. Search terms used included randomized controlled trial, controlled clinical trial, random allocation, double blind method, orthodontics, and laceback. Data were extracted using custom forms. Risk of bias assessment was made using the Cochrane Collaboration risk of bias tool. The quality of the evidence was also assessed using GRADE. Mean differences in incisor inclination and antero-posterior changes in incisor and molar position during alignment were calculated. Two studies involving 97 participants were found to be at low risk of bias and were included in the quantitative synthesis. The random effects meta-analysis demonstrated that the use of lacebacks was associated with 0.5 mm greater posterior movement of the incisors during alignment; this finding was of limited clinical importance and statistically non-significant [95 per cent confidence interval (CI): -1.25, 0.25, P = 0.19]. Little difference (0.46 mm) was also found between laceback and non-laceback groups with regards to mesial molar movement (95 per cent CI: -0.33, 1.24, P = 0.26). According to the GRADE assessment, the overall quality of evidence relating to the use of lacebacks was high. There is no evidence to support the use of lacebacks for the control of the sagittal position of the incisors during initial orthodontic alignment.

Comparative efficacy of pharmacological and non-pharmacological interventions in fibromyalgia syndrome: network meta-analysis

OBJECTIVES To synthesise the available evidence on pharmacological and non-pharmacological interventions recommended for fibromyalgia syndrome (FMS). METHODS Electronic databases including MEDLINE, PsycINFO, Scopus, the Cochrane Controlled Trials Registry and the Cochrane Library were searched for randomised controlled trials comparing any therapeutic approach as recommended in FMS guidelines (except complementary and alternative medicine) with control interventions in patients with FMS. Primary outcomes were pain and quality of life. Data extraction was done using standardised forms. RESULTS 102 trials in 14 982 patients and eight active interventions (tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors (SNRIs), the gamma-amino butyric acid analogue pregabalin, aerobic exercise, balneotherapy, cognitive behavioural therapy (CBT), multicomponent therapy) were included. Most of the trials were small and hampered by methodological quality, introducing heterogeneity and inconsistency in the network. When restricted to large trials with ≥100 patients per group, heterogeneity was low and benefits for SNRIs and pregabalin compared with placebo were statistically significant, but small and not clinically relevant. For non-pharmacological interventions, only one large trial of CBT was available. In medium-sized trials with ≥50 patients per group, multicomponent therapy showed small to moderate benefits over placebo, followed by aerobic exercise and CBT. CONCLUSIONS Benefits of pharmacological treatments in FMS are of questionable clinical relevance and evidence for benefits of non-pharmacological interventions is limited. A combination of pregabalin or SNRIs as pharmacological interventions and multicomponent therapy, aerobic exercise and CBT as non-pharmacological interventions seems most promising for the management of FMS.

Cancer patients' attitudes toward cancer trials

Background. Accurate measurement of attitudes toward participation in cancer treatment trials (CTs) and cancer prevention trials (CPTs) across varied groups could assist health researchers and educators when addressing attitudinal barriers to participation in these trials. ^ Methods. The Attitudes toward Cancer Trials Scales (ACTS) instrument development was based on a conceptual model developed from research literature, clinical practice experience, and empirical testing of items with a sample of 312 respondents. The ACTS contains two scales, the Cancer Trials (CT) scale (4 components; 18 items) and the Cancer Prevention Trials (CPT) scale (3 components; 16 items). Cronbach's alpha values for the CT and CPT scales, respectively, were 0.86 and 0.89. These two scales along with sociodemographic and cancer trial history variables were distributed in a mail survey of former patients of a large cancer research center. The disproportionate stratified probability sampling procedure yielded 925 usable responses (54% response rate). ^ Results. Prevalence of favorable attitudes toward CTs and CPTs was 66% and 69%, respectively. There were no significant differences in mean scale scores by cancer site or gender, but African Americans had more favorable attitudes toward CTs than European Americans. Multiple regression analysis indicated that older age, lower education level, and prior CT participation history were associated with more favorable attitudes toward CTs. Prior CT participation and prior CPT participation were associated with more favorable attitudes toward CPTs. Results also provided evidence of reliability and construct validity for both scales. ^ Conclusions. Middle age, higher education, and European American ethnicity are associated with less positive attitudes about participating in cancer treatment trials. Availability of a psychometrically sound instrument to measure attitudes may facilitate a better understanding decision making regarding participation in CTs and CPTs. It is this author's intention that the ACTS' scales will be used by other investigators to measure attitudes toward CTs and CPTs in various groups of persons, and that the many issues regarding participation in trials might become more explicit. ^

Cotrimoxazole prophylactic treatment prevents malaria in children in sub-Saharan Africa: systematic review and meta-analysis

OBJECTIVES Cotrimoxazole prophylactic treatment (CPT) prevents opportunistic infections in HIV-infected or HIV-exposed children, but estimates of the effectiveness in preventing malaria vary. We reviewed studies that examined the effect of CPT on incidence of malaria in children in sub-Saharan Africa. METHODS We searched PubMed and EMBASE for randomised controlled trials (RCTs) and cohort studies on the effect of CPT on incidence of malaria and mortality in children and extracted data on the prevalence of sulphadoxine-pyrimethamine resistance-conferring point mutations. Incidence rate ratios (IRR) from individual studies were combined using random effects meta-analysis; confounder-adjusted estimates were used for cohort studies. The importance of resistance was examined in meta-regression analyses. RESULTS Three RCTs and four cohort studies with 5039 children (1692 HIV-exposed; 2800 HIV-uninfected; 1486 HIV-infected) were included. Children on CPT were less likely to develop clinical malaria episodes than those without prophylaxis (combined IRR 0.37, 95% confidence interval: 0.21-0.66), but there was substantial between-study heterogeneity (I-squared = 94%, P < 0.001). The protective efficacy of CPT was highest in an RCT from Mali, where the prevalence of antifolate resistant plasmodia was low. In meta-regression analyses, there was some evidence that the efficacy of CPT declined with increasing levels of resistance. Mortality was reduced with CPT in an RCT from Zambia, but not in a cohort study from Côte d'Ivoire. CONCLUSIONS Cotrimoxazole prophylactic treatment reduces incidence of malaria and mortality in children in sub-Saharan Africa, but study designs, settings and results were heterogeneous. CPT appears to be beneficial for HIV-infected and HIV-exposed as well as HIV-uninfected children.

Incidence of anatomical variations and disease of the maxillary sinuses as identified by cone beam computed tomography: a systematic review.

PURPOSE To analyze available evidence on the incidence of anatomical variations or disease of the maxillary sinuses as identified by cone beam computed tomography (CBCT) in dentistry. MATERIALS AND METHODS A focused question was developed to search the electronic databases MEDLINE, EMBASE, the Cochrane Oral Health Group Trials Register, and CENTRAL and identify all relevant papers published between 1980 and January 19, 2013. Unpublished literature at ClinicalTrials.gov, in the National Research Register, and in the Pro-Quest Dissertation Abstracts and Thesis database was also included. Studies were included irrespective of language. These results were supplemented by hand and gray literature searches. RESULTS Twenty-two studies were identified. Twenty were retrospective cohort studies, one was a prospective cohort study, and one was a case control study. The main indication for CBCT was dental implant treatment planning, and the majority of studies used a small field of view for imaging. The most common anatomical variations included increased thickness of the sinus membrane, the presence of sinus septa, and pneumatization. Reported sinus disease frequency varied widely, ranging from 14.3% to 82%. There was a wide range in the reported prevalence of mucosal thickening related to apical pathology, the degree of lumenal opacification, features of sinusitis, and the presence of retention cysts and polyps. More pathologic findings in the maxillary sinus were reported in men than in women, and the medial wall and sinus floor were most frequently affected. CONCLUSION CBCT is used primarily to evaluate bony anatomy and to screen for overt pathology of the maxillary sinuses prior to dental implant treatment. Differences in the classification of mucosal findings are problematic in the consistent and valid assessment of health and disease of the maxillary sinus.

Enamel matrix derivative and bone grafts for periodontal regeneration of intrabony defects. A systematic review and meta-analysis

OBJECTIVE The aim of the present systematic review and meta-analysis was to assess the clinical efficacy of regenerative periodontal surgery of intrabony defects using a combination of enamel matrix derivative (EMD) and bone graft compared with that of EMD alone. MATERIALS AND METHODS The Cochrane Oral Health Group specialist trials, MEDLINE, and EMBASE databases were searched for entries up to February 2014. The primary outcome was gain of clinical attachment (CAL). Weighted means and forest plots were calculated for CAL gain, probing depth (PD), and gingival recession (REC). RESULTS Twelve studies reporting on 434 patients and 548 intrabony defects were selected for the analysis. Mean CAL gain amounted to 3.76 ± 1.07 mm (median 3.63 95 % CI 3.51-3.75) following treatment with a combination of EMD and bone graft and to 3.32 ± 1.04 mm (median 3.40; 95 % CI 3.28-3.52) following treatment with EMD alone. Mean PD reduction measured 4.22 ± 1.20 mm (median 4.10; 95 % CI 3.96-4.24) at sites treated with EMD and bone graft and yielded 4.12 ± 1.07 mm (median 4.00; 95 % CI 3.88-4.12) at sites treated with EMD alone. Mean REC increase amounted to 0.76 ± 0.42 mm (median 0.63; 95 % CI 0.58-0.68) at sites treated with EMD and bone graft and to 0.91 ± 0.26 mm (median 0.90; 95 % CI 0.87-0.93) at sites treated with EMD alone. CONCLUSIONS Within their limits, the present results indicate that the combination of EMD and bone grafts may result in additional clinical improvements in terms of CAL gain and PD reduction compared with those obtained with EMD alone. The potential influence of the chosen graft material or of the surgical procedure (i.e., flap design) on the clinical outcomes is unclear. CLINICAL RELEVANCE The present findings support the use of EMD and bone grafts for the treatment of intrabony periodontal defects.

Interventions for hirsutism (excluding laser and photoepilation therapy alone)

BACKGROUND Hirsutism occurs in 5% to 10% of women of reproductive age when there is excessive terminal hair growth in androgen-sensitive areas (male pattern). It is a distressing disorder with a major impact on quality of life. The most common cause is polycystic ovary syndrome. There are many treatment options, but it is not clear which are most effective. OBJECTIVES To assess the effects of interventions (except laser and light-based therapies alone) for hirsutism. SEARCH METHODS We searched the Cochrane Skin Group Specialised Register, CENTRAL (2014, Issue 6), MEDLINE (from 1946), EMBASE (from 1974), and five trials registers, and checked reference lists of included studies for additional trials. The last search was in June 2014. SELECTION CRITERIA Randomised controlled trials (RCTs) in hirsute women with polycystic ovary syndrome, idiopathic hirsutism, or idiopathic hyperandrogenism. DATA COLLECTION AND ANALYSIS Two independent authors carried out study selection, data extraction, 'Risk of bias' assessment, and analyses. MAIN RESULTS We included 157 studies (sample size 30 to 80) comprising 10,550 women (mean age 25 years). The majority of studies (123/157) were 'high', 30 'unclear', and four 'low' risk of bias. Lack of blinding was the most frequent source of bias. Treatment duration was six to 12 months. Forty-eight studies provided no usable or retrievable data, i.e. lack of separate data for hirsute women, conference proceedings, and losses to follow-up above 40%.Primary outcomes, 'participant-reported improvement of hirsutism' and 'change in health-related quality of life', were addressed in few studies, and adverse events in only half. In most comparisons there was insufficient evidence to determine if the number of reported adverse events differed. These included known adverse events: gastrointestinal discomfort, breast tenderness, reduced libido, dry skin (flutamide and finasteride); irregular bleeding (spironolactone); nausea, diarrhoea, bloating (metformin); hot flushes, decreased libido, vaginal dryness, headaches (gonadotropin-releasing hormone (GnRH) analogues)).Clinician's evaluation of hirsutism and change in androgen levels were addressed in most comparisons, change in body mass index (BMI) and improvement of other clinical signs of hyperandrogenism in one-third of studies.The quality of evidence was moderate to very low for most outcomes.There was low quality evidence for the effect of two oral contraceptive pills (OCPs) (ethinyl estradiol + cyproterone acetate versus ethinyl estradiol + desogestrel) on change from baseline of Ferriman-Gallwey scores. The mean difference (MD) was -1.84 (95% confidence interval (CI) -3.86 to 0.18).There was very low quality evidence that flutamide 250 mg, twice daily, reduced Ferriman-Gallwey scores more effectively than placebo (MD -7.60, 95% CI -10.53 to -4.67 and MD -7.20, 95% CI -10.15 to -4.25). Participants' evaluations in one study with 20 participants confirmed these results (risk ratio (RR) 17.00, 95% CI 1.11 to 259.87).Spironolactone 100 mg daily was more effective than placebo in reducing Ferriman-Gallwey scores (MD -7.69, 95% CI -10.12 to -5.26) (low quality evidence). It showed similar effectiveness to flutamide in two studies (MD -1.90, 95% CI -5.01 to 1.21 and MD 0.49, 95% CI -1.99 to 2.97) (very low quality evidence), as well as to finasteride in two studies (MD 1.49, 95% CI -0.58 to 3.56 and MD 0.40, 95% CI -1.18 to 1.98) (low quality evidence).Although there was very low quality evidence of a difference in reduction of Ferriman-Gallwey scores for finasteride 5 mg to 7.5 mg daily versus placebo (MD -5.73, 95% CI -6.87 to -4.58), it was unlikely it was clinically meaningful. These results were reinforced by participants' assessments (RR 2.06, 95% CI 0.99 to 4.29 and RR 11.00, 95% CI 0.69 to 175.86). However, finasteride showed inconsistent results in comparisons with other treatments, and no firm conclusions could be reached.Metformin demonstrated no benefit over placebo in reduction of Ferriman-Gallwey scores (MD 0.05, 95% CI -1.02 to 1.12), but the quality of evidence was low. Results regarding the effectiveness of GnRH analogues were inconsistent, varying from minimal to important improvements.We were unable to pool data for OCPs with cyproterone acetate 20 mg to 100 mg due to clinical and methodological heterogeneity between studies. However, addition of cyproterone acetate to OCPs provided greater reductions in Ferriman-Gallwey scores.Two studies, comparing finasteride 5 mg and spironolactone 100 mg, did not show differences in participant assessments and reduction of Ferriman-Gallwey scores (low quality evidence). Ferriman-Gallwey scores from three studies comparing flutamide versus metformin could not be pooled (I² = 62%). One study comparing flutamide 250 mg twice daily with metformin 850 mg twice daily for 12 months, which reached a higher cumulative dosage than two other studies evaluating this comparison, showed flutamide to be more effective (MD -6.30, 95% CI -9.83 to -2.77) (very low quality evidence). Data showing reductions in Ferriman-Gallwey scores could not be pooled for four studies comparing finasteride with flutamide as the results were inconsistent (I² = 67%).Studies examining effects of hypocaloric diets reported reductions in BMI, but which did not result in reductions in Ferriman-Gallwey scores. Although certain cosmetic measures are commonly used, we did not identify any relevant RCTs. AUTHORS' CONCLUSIONS Treatments may need to incorporate pharmacological therapies, cosmetic procedures, and psychological support. For mild hirsutism there is evidence of limited quality that OCPs are effective. Flutamide 250 mg twice daily and spironolactone 100 mg daily appeared to be effective and safe, albeit the evidence was low to very low quality. Finasteride 5 mg daily showed inconsistent results in different comparisons, therefore no firm conclusions can be made. As the side effects of antiandrogens and finasteride are well known, these should be accounted for in any clinical decision-making. There was low quality evidence that metformin was ineffective for hirsutism and although GnRH analogues showed inconsistent results in reducing hirsutism they do have significant side effects.Further research should consist of well-designed, rigorously reported, head-to-head trials examining OCPs combined with antiandrogens or 5α-reductase inhibitor against OCP monotherapy, as well as the different antiandrogens and 5α-reductase inhibitors against each other. Outcomes should be based on standardised scales of participants' assessment of treatment efficacy, with a greater emphasis on change in quality of life as a result of treatment.

Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis.

BACKGROUND Non-steroidal anti-inflammatory drugs (NSAIDs) are the backbone of osteoarthritis pain management. We aimed to assess the effectiveness of different preparations and doses of NSAIDs on osteoarthritis pain in a network meta-analysis. METHODS For this network meta-analysis, we considered randomised trials comparing any of the following interventions: NSAIDs, paracetamol, or placebo, for the treatment of osteoarthritis pain. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) and the reference lists of relevant articles for trials published between Jan 1, 1980, and Feb 24, 2015, with at least 100 patients per group. The prespecified primary and secondary outcomes were pain and physical function, and were extracted in duplicate for up to seven timepoints after the start of treatment. We used an extension of multivariable Bayesian random effects models for mixed multiple treatment comparisons with a random effect at the level of trials. For the primary analysis, a random walk of first order was used to account for multiple follow-up outcome data within a trial. Preparations that used different total daily dose were considered separately in the analysis. To assess a potential dose-response relation, we used preparation-specific covariates assuming linearity on log relative dose. FINDINGS We identified 8973 manuscripts from our search, of which 74 randomised trials with a total of 58 556 patients were included in this analysis. 23 nodes concerning seven different NSAIDs or paracetamol with specific daily dose of administration or placebo were considered. All preparations, irrespective of dose, improved point estimates of pain symptoms when compared with placebo. For six interventions (diclofenac 150 mg/day, etoricoxib 30 mg/day, 60 mg/day, and 90 mg/day, and rofecoxib 25 mg/day and 50 mg/day), the probability that the difference to placebo is at or below a prespecified minimum clinically important effect for pain reduction (effect size [ES] -0·37) was at least 95%. Among maximally approved daily doses, diclofenac 150 mg/day (ES -0·57, 95% credibility interval [CrI] -0·69 to -0·46) and etoricoxib 60 mg/day (ES -0·58, -0·73 to -0·43) had the highest probability to be the best intervention, both with 100% probability to reach the minimum clinically important difference. Treatment effects increased as drug dose increased, but corresponding tests for a linear dose effect were significant only for celecoxib (p=0·030), diclofenac (p=0·031), and naproxen (p=0·026). We found no evidence that treatment effects varied over the duration of treatment. Model fit was good, and between-trial heterogeneity and inconsistency were low in all analyses. All trials were deemed to have a low risk of bias for blinding of patients. Effect estimates did not change in sensitivity analyses with two additional statistical models and accounting for methodological quality criteria in meta-regression analysis. INTERPRETATION On the basis of the available data, we see no role for single-agent paracetamol for the treatment of patients with osteoarthritis irrespective of dose. We provide sound evidence that diclofenac 150 mg/day is the most effective NSAID available at present, in terms of improving both pain and function. Nevertheless, in view of the safety profile of these drugs, physicians need to consider our results together with all known safety information when selecting the preparation and dose for individual patients. FUNDING Swiss National Science Foundation (grant number 405340-104762) and Arco Foundation, Switzerland.

Differential Activity of the KRAS Oncogene by Method of Activation: Implications for Signaling and Therapeutic Intervention

Despite having been identified over thirty years ago and definitively established as having a critical role in driving tumor growth and predicting for resistance to therapy, the KRAS oncogene remains a target in cancer for which there is no effective treatment. KRas is activated b y mutations at a few sites, primarily amino acid substitutions at codon 12 which promote a constitutively active state. I have found that different amino acid substitutions at codon 12 can activate different KRas downstream signaling pathways, determine clonogenic growth potential and determine patient response to molecularly targeted therapies. Computer modeling of the KRas structure shows that different amino acids substituted at the codon 12 position influences how KRas interacts with its effecters. In the absence of a direct inhibitor of mutant KRas several agents have recently entered clinical trials alone and in combination directly targeting two of the common downstream effecter pathways of KRas, namely the Mapk pathway and the Akt pathway. These inhibitors were evaluated for efficacy against different KRAS activating mutations. An isogenic panel of colorectal cells with wild type KRas replaced with KRas G12C, G12D, or G12V at the endogenous loci differed in sensitivity to Mek and Akt inhibition. In contrast, screening was performed in a broad panel of lung cell lines alone and no correlation was seen between types of activating KRAS mutation due to concurrent oncogenic lesions. To find a new method to inhibit KRAS driven tumors, siRNA screens were performed in isogenic lines with and without active KRas. The knockdown of CNKSR1 (CNK1) showed selective growth inhibition in cells with an oncogenic KRAS. The deletion of CNK1 reduces expression of mitotic cell cycle proteins and arrests cells with active KRas in the G1 phase of the cell cycle similar to the deletion of an activated KRas regardless of activating substitution. CNK1 has a PH domain responsible for localizing it to membrane lipids making KRas potentially amenable to inhibition with small molecules. The work has identified a series of small molecules capable of binding to this PH domain and inhibiting CNK1 facilitated KRas signaling.

Localization and Tracking in Energy-Constrained Networks with Dynamic Connectivity

Systems used for target localization, such as goods, individuals, or animals, commonly rely on operational means to meet the final application demands. However, what would happen if some means were powered up randomly by harvesting systems? And what if those devices not randomly powered had their duty cycles restricted? Under what conditions would such an operation be tolerable in localization services? What if the references provided by nodes in a tracking problem were distorted? Moreover, there is an underlying topic common to the previous questions regarding the transfer of conceptual models to reality in field tests: what challenges are faced upon deploying a localization network that integrates energy harvesting modules? The application scenario of the system studied is a traditional herding environment of semi domesticated reindeer (Rangifer tarandus tarandus) in northern Scandinavia. In these conditions, information on approximate locations of reindeer is as important as environmental preservation. Herders also need cost-effective devices capable of operating unattended in, sometimes, extreme weather conditions. The analyses developed are worthy not only for the specific application environment presented, but also because they may serve as an approach to performance of navigation systems in absence of reasonably accurate references like the ones of the Global Positioning System (GPS). A number of energy-harvesting solutions, like thermal and radio-frequency harvesting, do not commonly provide power beyond one milliwatt. When they do, battery buffers may be needed (as it happens with solar energy) which may raise costs and make systems more dependent on environmental temperatures. In general, given our problem, a harvesting system is needed that be capable of providing energy bursts of, at least, some milliwatts. Many works on localization problems assume that devices have certain capabilities to determine unknown locations based on range-based techniques or fingerprinting which cannot be assumed in the approach considered herein. The system presented is akin to range-free techniques, but goes to the extent of considering very low node densities: most range-free techniques are, therefore, not applicable. Animal localization, in particular, uses to be supported by accurate devices such as GPS collars which deplete batteries in, maximum, a few days. Such short-life solutions are not particularly desirable in the framework considered. In tracking, the challenge may times addressed aims at attaining high precision levels from complex reliable hardware and thorough processing techniques. One of the challenges in this Thesis is the use of equipment with just part of its facilities in permanent operation, which may yield high input noise levels in the form of distorted reference points. The solution presented integrates a kinetic harvesting module in some nodes which are expected to be a majority in the network. These modules are capable of providing power bursts of some milliwatts which suffice to meet node energy demands. The usage of harvesting modules in the aforementioned conditions makes the system less dependent on environmental temperatures as no batteries are used in nodes with harvesters--it may be also an advantage in economic terms. There is a second kind of nodes. They are battery powered (without kinetic energy harvesters), and are, therefore, dependent on temperature and battery replacements. In addition, their operation is constrained by duty cycles in order to extend node lifetime and, consequently, their autonomy. There is, in turn, a third type of nodes (hotspots) which can be static or mobile. They are also battery-powered, and are used to retrieve information from the network so that it is presented to users. The system operational chain starts at the kinetic-powered nodes broadcasting their own identifier. If an identifier is received at a battery-powered node, the latter stores it for its records. Later, as the recording node meets a hotspot, its full record of detections is transferred to the hotspot. Every detection registry comprises, at least, a node identifier and the position read from its GPS module by the battery-operated node previously to detection. The characteristics of the system presented make the aforementioned operation own certain particularities which are also studied. First, identifier transmissions are random as they depend on movements at kinetic modules--reindeer movements in our application. Not every movement suffices since it must overcome a certain energy threshold. Second, identifier transmissions may not be heard unless there is a battery-powered node in the surroundings. Third, battery-powered nodes do not poll continuously their GPS module, hence localization errors rise even more. Let's recall at this point that such behavior is tight to the aforementioned power saving policies to extend node lifetime. Last, some time is elapsed between the instant an identifier random transmission is detected and the moment the user is aware of such a detection: it takes some time to find a hotspot. Tracking is posed as a problem of a single kinetically-powered target and a population of battery-operated nodes with higher densities than before in localization. Since the latter provide their approximate positions as reference locations, the study is again focused on assessing the impact of such distorted references on performance. Unlike in localization, distance-estimation capabilities based on signal parameters are assumed in this problem. Three variants of the Kalman filter family are applied in this context: the regular Kalman filter, the alpha-beta filter, and the unscented Kalman filter. The study enclosed hereafter comprises both field tests and simulations. Field tests were used mainly to assess the challenges related to power supply and operation in extreme conditions as well as to model nodes and some aspects of their operation in the application scenario. These models are the basics of the simulations developed later. The overall system performance is analyzed according to three metrics: number of detections per kinetic node, accuracy, and latency. The links between these metrics and the operational conditions are also discussed and characterized statistically. Subsequently, such statistical characterization is used to forecast performance figures given specific operational parameters. In tracking, also studied via simulations, nonlinear relationships are found between accuracy and duty cycles and cluster sizes of battery-operated nodes. The solution presented may be more complex in terms of network structure than existing solutions based on GPS collars. However, its main gain lies on taking advantage of users' error tolerance to reduce costs and become more environmentally friendly by diminishing the potential amount of batteries that can be lost. Whether it is applicable or not depends ultimately on the conditions and requirements imposed by users' needs and operational environments, which is, as it has been explained, one of the topics of this Thesis.

Contributions to the Resilience Management in the Internet of Things

El auge del "Internet de las Cosas" (IoT, "Internet of Things") y sus tecnologías asociadas han permitido su aplicación en diversos dominios de la aplicación, entre los que se encuentran la monitorización de ecosistemas forestales, la gestión de catástrofes y emergencias, la domótica, la automatización industrial, los servicios para ciudades inteligentes, la eficiencia energética de edificios, la detección de intrusos, la gestión de desastres y emergencias o la monitorización de señales corporales, entre muchas otras. La desventaja de una red IoT es que una vez desplegada, ésta queda desatendida, es decir queda sujeta, entre otras cosas, a condiciones climáticas cambiantes y expuestas a catástrofes naturales, fallos de software o hardware, o ataques maliciosos de terceros, por lo que se puede considerar que dichas redes son propensas a fallos. El principal requisito de los nodos constituyentes de una red IoT es que estos deben ser capaces de seguir funcionando a pesar de sufrir errores en el propio sistema. La capacidad de la red para recuperarse ante fallos internos y externos inesperados es lo que se conoce actualmente como "Resiliencia" de la red. Por tanto, a la hora de diseñar y desplegar aplicaciones o servicios para IoT, se espera que la red sea tolerante a fallos, que sea auto-configurable, auto-adaptable, auto-optimizable con respecto a nuevas condiciones que puedan aparecer durante su ejecución. Esto lleva al análisis de un problema fundamental en el estudio de las redes IoT, el problema de la "Conectividad". Se dice que una red está conectada si todo par de nodos en la red son capaces de encontrar al menos un camino de comunicación entre ambos. Sin embargo, la red puede desconectarse debido a varias razones, como que se agote la batería, que un nodo sea destruido, etc. Por tanto, se hace necesario gestionar la resiliencia de la red con el objeto de mantener la conectividad entre sus nodos, de tal manera que cada nodo IoT sea capaz de proveer servicios continuos, a otros nodos, a otras redes o, a otros servicios y aplicaciones. En este contexto, el objetivo principal de esta tesis doctoral se centra en el estudio del problema de conectividad IoT, más concretamente en el desarrollo de modelos para el análisis y gestión de la Resiliencia, llevado a la práctica a través de las redes WSN, con el fin de mejorar la capacidad la tolerancia a fallos de los nodos que componen la red. Este reto se aborda teniendo en cuenta dos enfoques distintos, por una parte, a diferencia de otro tipo de redes de dispositivos convencionales, los nodos en una red IoT son propensos a perder la conexión, debido a que se despliegan en entornos aislados, o en entornos con condiciones extremas; por otra parte, los nodos suelen ser recursos con bajas capacidades en términos de procesamiento, almacenamiento y batería, entre otros, por lo que requiere que el diseño de la gestión de su resiliencia sea ligero, distribuido y energéticamente eficiente. En este sentido, esta tesis desarrolla técnicas auto-adaptativas que permiten a una red IoT, desde la perspectiva del control de su topología, ser resiliente ante fallos en sus nodos. Para ello, se utilizan técnicas basadas en lógica difusa y técnicas de control proporcional, integral y derivativa (PID - "proportional-integral-derivative"), con el objeto de mejorar la conectividad de la red, teniendo en cuenta que el consumo de energía debe preservarse tanto como sea posible. De igual manera, se ha tenido en cuenta que el algoritmo de control debe ser distribuido debido a que, en general, los enfoques centralizados no suelen ser factibles a despliegues a gran escala. El presente trabajo de tesis implica varios retos que conciernen a la conectividad de red, entre los que se incluyen: la creación y el análisis de modelos matemáticos que describan la red, una propuesta de sistema de control auto-adaptativo en respuesta a fallos en los nodos, la optimización de los parámetros del sistema de control, la validación mediante una implementación siguiendo un enfoque de ingeniería del software y finalmente la evaluación en una aplicación real. Atendiendo a los retos anteriormente mencionados, el presente trabajo justifica, mediante una análisis matemático, la relación existente entre el "grado de un nodo" (definido como el número de nodos en la vecindad del nodo en cuestión) y la conectividad de la red, y prueba la eficacia de varios tipos de controladores que permiten ajustar la potencia de trasmisión de los nodos de red en respuesta a eventuales fallos, teniendo en cuenta el consumo de energía como parte de los objetivos de control. Así mismo, este trabajo realiza una evaluación y comparación con otros algoritmos representativos; en donde se demuestra que el enfoque desarrollado es más tolerante a fallos aleatorios en los nodos de la red, así como en su eficiencia energética. Adicionalmente, el uso de algoritmos bioinspirados ha permitido la optimización de los parámetros de control de redes dinámicas de gran tamaño. Con respecto a la implementación en un sistema real, se han integrado las propuestas de esta tesis en un modelo de programación OSGi ("Open Services Gateway Initiative") con el objeto de crear un middleware auto-adaptativo que mejore la gestión de la resiliencia, especialmente la reconfiguración en tiempo de ejecución de componentes software cuando se ha producido un fallo. Como conclusión, los resultados de esta tesis doctoral contribuyen a la investigación teórica y, a la aplicación práctica del control resiliente de la topología en redes distribuidas de gran tamaño. Los diseños y algoritmos presentados pueden ser vistos como una prueba novedosa de algunas técnicas para la próxima era de IoT. A continuación, se enuncian de forma resumida las principales contribuciones de esta tesis: (1) Se han analizado matemáticamente propiedades relacionadas con la conectividad de la red. Se estudia, por ejemplo, cómo varía la probabilidad de conexión de la red al modificar el alcance de comunicación de los nodos, así como cuál es el mínimo número de nodos que hay que añadir al sistema desconectado para su re-conexión. (2) Se han propuesto sistemas de control basados en lógica difusa para alcanzar el grado de los nodos deseado, manteniendo la conectividad completa de la red. Se han evaluado diferentes tipos de controladores basados en lógica difusa mediante simulaciones, y los resultados se han comparado con otros algoritmos representativos. (3) Se ha investigado más a fondo, dando un enfoque más simple y aplicable, el sistema de control de doble bucle, y sus parámetros de control se han optimizado empleando algoritmos heurísticos como el método de la entropía cruzada (CE, "Cross Entropy"), la optimización por enjambre de partículas (PSO, "Particle Swarm Optimization"), y la evolución diferencial (DE, "Differential Evolution"). (4) Se han evaluado mediante simulación, la mayoría de los diseños aquí presentados; además, parte de los trabajos se han implementado y validado en una aplicación real combinando técnicas de software auto-adaptativo, como por ejemplo las de una arquitectura orientada a servicios (SOA, "Service-Oriented Architecture"). ABSTRACT The advent of the Internet of Things (IoT) enables a tremendous number of applications, such as forest monitoring, disaster management, home automation, factory automation, smart city, etc. However, various kinds of unexpected disturbances may cause node failure in the IoT, for example battery depletion, software/hardware malfunction issues and malicious attacks. So, it can be considered that the IoT is prone to failure. The ability of the network to recover from unexpected internal and external failures is known as "resilience" of the network. Resilience usually serves as an important non-functional requirement when designing IoT, which can further be broken down into "self-*" properties, such as self-adaptive, self-healing, self-configuring, self-optimization, etc. One of the consequences that node failure brings to the IoT is that some nodes may be disconnected from others, such that they are not capable of providing continuous services for other nodes, networks, and applications. In this sense, the main objective of this dissertation focuses on the IoT connectivity problem. A network is regarded as connected if any pair of different nodes can communicate with each other either directly or via a limited number of intermediate nodes. More specifically, this thesis focuses on the development of models for analysis and management of resilience, implemented through the Wireless Sensor Networks (WSNs), which is a challenging task. On the one hand, unlike other conventional network devices, nodes in the IoT are more likely to be disconnected from each other due to their deployment in a hostile or isolated environment. On the other hand, nodes are resource-constrained in terms of limited processing capability, storage and battery capacity, which requires that the design of the resilience management for IoT has to be lightweight, distributed and energy-efficient. In this context, the thesis presents self-adaptive techniques for IoT, with the aim of making the IoT resilient against node failures from the network topology control point of view. The fuzzy-logic and proportional-integral-derivative (PID) control techniques are leveraged to improve the network connectivity of the IoT in response to node failures, meanwhile taking into consideration that energy consumption must be preserved as much as possible. The control algorithm itself is designed to be distributed, because the centralized approaches are usually not feasible in large scale IoT deployments. The thesis involves various aspects concerning network connectivity, including: creation and analysis of mathematical models describing the network, proposing self-adaptive control systems in response to node failures, control system parameter optimization, implementation using the software engineering approach, and evaluation in a real application. This thesis also justifies the relations between the "node degree" (the number of neighbor(s) of a node) and network connectivity through mathematic analysis, and proves the effectiveness of various types of controllers that can adjust power transmission of the IoT nodes in response to node failures. The controllers also take into consideration the energy consumption as part of the control goals. The evaluation is performed and comparison is made with other representative algorithms. The simulation results show that the proposals in this thesis can tolerate more random node failures and save more energy when compared with those representative algorithms. Additionally, the simulations demonstrate that the use of the bio-inspired algorithms allows optimizing the parameters of the controller. With respect to the implementation in a real system, the programming model called OSGi (Open Service Gateway Initiative) is integrated with the proposals in order to create a self-adaptive middleware, especially reconfiguring the software components at runtime when failures occur. The outcomes of this thesis contribute to theoretic research and practical applications of resilient topology control for large and distributed networks. The presented controller designs and optimization algorithms can be viewed as novel trials of the control and optimization techniques for the coming era of the IoT. The contributions of this thesis can be summarized as follows: (1) Mathematically, the fault-tolerant probability of a large-scale stochastic network is analyzed. It is studied how the probability of network connectivity depends on the communication range of the nodes, and what is the minimum number of neighbors to be added for network re-connection. (2) A fuzzy-logic control system is proposed, which obtains the desired node degree and in turn maintains the network connectivity when it is subject to node failures. There are different types of fuzzy-logic controllers evaluated by simulations, and the results demonstrate the improvement of fault-tolerant capability as compared to some other representative algorithms. (3) A simpler but more applicable approach, the two-loop control system is further investigated, and its control parameters are optimized by using some heuristic algorithms such as Cross Entropy (CE), Particle Swarm Optimization (PSO), and Differential Evolution (DE). (4) Most of the designs are evaluated by means of simulations, but part of the proposals are implemented and tested in a real-world application by combining the self-adaptive software technique and the control algorithms which are presented in this thesis.

Co-simulation Methodologies for Hybrid and Electric Vehicle Dynamics

In recent decades, full electric and hybrid electric vehicles have emerged as an alternative to conventional cars due to a range of factors, including environmental and economic aspects. These vehicles are the result of considerable efforts to seek ways of reducing the use of fossil fuel for vehicle propulsion. Sophisticated technologies such as hybrid and electric powertrains require careful study and optimization. Mathematical models play a key role at this point. Currently, many advanced mathematical analysis tools, as well as computer applications have been built for vehicle simulation purposes. Given the great interest of hybrid and electric powertrains, along with the increasing importance of reliable computer-based models, the author decided to integrate both aspects in the research purpose of this work. Furthermore, this is one of the first final degree projects held at the ETSII (Higher Technical School of Industrial Engineers) that covers the study of hybrid and electric propulsion systems. The present project is based on MBS3D 2.0, a specialized software for the dynamic simulation of multibody systems developed at the UPM Institute of Automobile Research (INSIA). Automobiles are a clear example of complex multibody systems, which are present in nearly every field of engineering. The work presented here benefits from the availability of MBS3D software. This program has proven to be a very efficient tool, with a highly developed underlying mathematical formulation. On this basis, the focus of this project is the extension of MBS3D features in order to be able to perform dynamic simulations of hybrid and electric vehicle models. This requires the joint simulation of the mechanical model of the vehicle, together with the model of the hybrid or electric powertrain. These sub-models belong to completely different physical domains. In fact the powertrain consists of energy storage systems, electrical machines and power electronics, connected to purely mechanical components (wheels, suspension, transmission, clutch…). The challenge today is to create a global vehicle model that is valid for computer simulation. Therefore, the main goal of this project is to apply co-simulation methodologies to a comprehensive model of an electric vehicle, where sub-models from different areas of engineering are coupled. The created electric vehicle (EV) model consists of a separately excited DC electric motor, a Li-ion battery pack, a DC/DC chopper converter and a multibody vehicle model. Co-simulation techniques allow car designers to simulate complex vehicle architectures and behaviors, which are usually difficult to implement in a real environment due to safety and/or economic reasons. In addition, multi-domain computational models help to detect the effects of different driving patterns and parameters and improve the models in a fast and effective way. Automotive designers can greatly benefit from a multidisciplinary approach of new hybrid and electric vehicles. In this case, the global electric vehicle model includes an electrical subsystem and a mechanical subsystem. The electrical subsystem consists of three basic components: electric motor, battery pack and power converter. A modular representation is used for building the dynamic model of the vehicle drivetrain. This means that every component of the drivetrain (submodule) is modeled separately and has its own general dynamic model, with clearly defined inputs and outputs. Then, all the particular submodules are assembled according to the drivetrain configuration and, in this way, the power flow across the components is completely determined. Dynamic models of electrical components are often based on equivalent circuits, where Kirchhoff’s voltage and current laws are applied to draw the algebraic and differential equations. Here, Randles circuit is used for dynamic modeling of the battery and the electric motor is modeled through the analysis of the equivalent circuit of a separately excited DC motor, where the power converter is included. The mechanical subsystem is defined by MBS3D equations. These equations consider the position, velocity and acceleration of all the bodies comprising the vehicle multibody system. MBS3D 2.0 is entirely written in MATLAB and the structure of the program has been thoroughly studied and understood by the author. MBS3D software is adapted according to the requirements of the applied co-simulation method. Some of the core functions are modified, such as integrator and graphics, and several auxiliary functions are added in order to compute the mathematical model of the electrical components. By coupling and co-simulating both subsystems, it is possible to evaluate the dynamic interaction among all the components of the drivetrain. ‘Tight-coupling’ method is used to cosimulate the sub-models. This approach integrates all subsystems simultaneously and the results of the integration are exchanged by function-call. This means that the integration is done jointly for the mechanical and the electrical subsystem, under a single integrator and then, the speed of integration is determined by the slower subsystem. Simulations are then used to show the performance of the developed EV model. However, this project focuses more on the validation of the computational and mathematical tool for electric and hybrid vehicle simulation. For this purpose, a detailed study and comparison of different integrators within the MATLAB environment is done. Consequently, the main efforts are directed towards the implementation of co-simulation techniques in MBS3D software. In this regard, it is not intended to create an extremely precise EV model in terms of real vehicle performance, although an acceptable level of accuracy is achieved. The gap between the EV model and the real system is filled, in a way, by introducing the gas and brake pedals input, which reflects the actual driver behavior. This input is included directly in the differential equations of the model, and determines the amount of current provided to the electric motor. For a separately excited DC motor, the rotor current is proportional to the traction torque delivered to the car wheels. Therefore, as it occurs in the case of real vehicle models, the propulsion torque in the mathematical model is controlled through acceleration and brake pedal commands. The designed transmission system also includes a reduction gear that adapts the torque coming for the motor drive and transfers it. The main contribution of this project is, therefore, the implementation of a new calculation path for the wheel torques, based on performance characteristics and outputs of the electric powertrain model. Originally, the wheel traction and braking torques were input to MBS3D through a vector directly computed by the user in a MATLAB script. Now, they are calculated as a function of the motor current which, in turn, depends on the current provided by the battery pack across the DC/DC chopper converter. The motor and battery currents and voltages are the solutions of the electrical ODE (Ordinary Differential Equation) system coupled to the multibody system. Simultaneously, the outputs of MBS3D model are the position, velocity and acceleration of the vehicle at all times. The motor shaft speed is computed from the output vehicle speed considering the wheel radius, the gear reduction ratio and the transmission efficiency. This motor shaft speed, somehow available from MBS3D model, is then introduced in the differential equations corresponding to the electrical subsystem. In this way, MBS3D and the electrical powertrain model are interconnected and both subsystems exchange values resulting as expected with tight-coupling approach.When programming mathematical models of complex systems, code optimization is a key step in the process. A way to improve the overall performance of the integration, making use of C/C++ as an alternative programming language, is described and implemented. Although this entails a higher computational burden, it leads to important advantages regarding cosimulation speed and stability. In order to do this, it is necessary to integrate MATLAB with another integrated development environment (IDE), where C/C++ code can be generated and executed. In this project, C/C++ files are programmed in Microsoft Visual Studio and the interface between both IDEs is created by building C/C++ MEX file functions. These programs contain functions or subroutines that can be dynamically linked and executed from MATLAB. This process achieves reductions in simulation time up to two orders of magnitude. The tests performed with different integrators, also reveal the stiff character of the differential equations corresponding to the electrical subsystem, and allow the improvement of the cosimulation process. When varying the parameters of the integration and/or the initial conditions of the problem, the solutions of the system of equations show better dynamic response and stability, depending on the integrator used. Several integrators, with variable and non-variable step-size, and for stiff and non-stiff problems are applied to the coupled ODE system. Then, the results are analyzed, compared and discussed. From all the above, the project can be divided into four main parts: 1. Creation of the equation-based electric vehicle model; 2. Programming, simulation and adjustment of the electric vehicle model; 3. Application of co-simulation methodologies to MBS3D and the electric powertrain subsystem; and 4. Code optimization and study of different integrators. Additionally, in order to deeply understand the context of the project, the first chapters include an introduction to basic vehicle dynamics, current classification of hybrid and electric vehicles and an explanation of the involved technologies such as brake energy regeneration, electric and non-electric propulsion systems for EVs and HEVs (hybrid electric vehicles) and their control strategies. Later, the problem of dynamic modeling of hybrid and electric vehicles is discussed. The integrated development environment and the simulation tool are also briefly described. The core chapters include an explanation of the major co-simulation methodologies and how they have been programmed and applied to the electric powertrain model together with the multibody system dynamic model. Finally, the last chapters summarize the main results and conclusions of the project and propose further research topics. In conclusion, co-simulation methodologies are applicable within the integrated development environments MATLAB and Visual Studio, and the simulation tool MBS3D 2.0, where equation-based models of multidisciplinary subsystems, consisting of mechanical and electrical components, are coupled and integrated in a very efficient way.