Impact of disease and treatments on growth and puberty of pediatric patients with inflammatory bowel disease.

Growth retardation, associated with delayed puberty, is a frequent feature in pediatric patients with inflammatory bowel disease (IBD), especially with Crohn's disease. It is mainly induced by malnutrition and the effects of the inflammatory process on the growth hormone/insulin-like growth factor-1 axis or on the growth plate. Therefore, control of disease activity and mucosal healing are paramount to promote growth and adequate pubertal onset. Current therapeutic strategies for maintenance in IBD include anti-inflammatory drugs, immunosuppressives, and, more recently, biologic agents. Although these treatments are efficient in minimizing inflammation and inducing prolonged remission, their long-term effects on growth and final height remain controversial. Furthermore, glucocorticoid therapy, even though very efficient in inducing remission, clearly shows deleterious effects on growth, which is not the case for exclusive enteral nutrition showing comparable results regarding induction of remission. Thus regular assessment of weight, height and pubertal stage is essential in children and adolescents with chronic disease, namely IBD.

Anti-tumor necrosis factor drug survival in axial spondyloarthritis is independent of the classification criteria.

To compare the impact of meeting specific classification criteria [modified New York (mNY), European Spondyloarthropathy Study Group (ESSG), and Assessment of SpondyloArthritis international Society (ASAS) criteria] on anti-tumor necrosis factor (anti-TNF) drug retention, and to determine predictive factors of better drug survival. All patients fulfilling the ESSG criteria for axial spondyloarthritis (SpA) with available data on the axial ASAS and mNY criteria, and who had received at least one anti-TNF treatment were retrospectively retrieved in a single academic institution in Switzerland. Drug retention was computed using survival analysis (Kaplan-Meier), adjusted for potential confounders. Of the 137 patients classified as having axial SpA using the ESSG criteria, 112 also met the ASAS axial SpA criteria, and 77 fulfilled the mNY criteria. Drug retention rates at 12 and 24 months for the first biologic therapy were not significantly different between the diagnostic groups. Only the small ASAS non-classified axial SpA group (25 patients) showed a nonsignificant trend toward shorter drug survival. Elevated CRP level, but not the presence of bone marrow edema on magnetic resonance imaging (MRI) scans, was associated with significantly better drug retention (OR 7.9, ICR 4-14). In this cohort, anti-TNF drug survival was independent of the classification criteria. Elevated CRP level, but not positive MRI, was associated with better drug retention.

Impact of clinical practice guidelines on priorisation for intensive care beds allocation in high-risk acute coronary syndrome patients: does age play a role?

QUESTION UNDER STUDY: To assess which high-risk acute coronary syndrome (ACS) patient characteristics played a role in prioritising access to intensive care unit (ICU), and whether introducing clinical practice guidelines (CPG) explicitly stating ICU admission criteria altered this practice. PATIENTS AND METHODS: All consecutive patients with ACS admitted to our medical emergency centre over 3 months before and after CPG implementation were prospectively assessed. The impact of demographic and clinical characteristics (age, gender, cardiovascular risk factors, and clinical parameters upon admission) on ICU hospitalisation of high-risk patients (defined as retrosternal pain of prolonged duration with ECG changes and/or positive troponin blood level) was studied by logistic regression. RESULTS: Before and after CPG implementation, 328 and 364 patients, respectively, were assessed for suspicion of ACS. Before CPG implementation, 36 of the 81 high-risk patients (44.4%) were admitted to ICU. After CPG implementation, 35 of the 90 high-risk patients (38.9%) were admitted to ICU. Male patients were more frequently admitted to ICU before CPG implementation (OR=7.45, 95% CI 2.10-26.44), but not after (OR=0.73, 95% CI 0.20-2.66). Age played a significant role in both periods (OR=1.57, 95% CI 1.24-1.99), both young and advanced ages significantly reducing ICU admission, but to a lesser extent after CPG implementation. CONCLUSION: Prioritisation of access to ICU for high-risk ACS patients was age-dependent, but focused on the cardiovascular risk factor profile. CPG implementation explicitly stating ICU admission criteria decreased discrimination against women, but other factors are likely to play a role in bed allocation.

MMP-9 as predictive factor for response and progression free survival in breast cancer patients treated with bevacizumab and pegylated liposomal doxorubicin. A multicenter, single-arm phase II trial (SAKK24/06). On behalf of the Swiss Group for Clinical Cancer Research (SAKK).

The benefit of bevacizumab (Bv) has been shown in different tumors including colorectal cancer, renal cancer, pulmonary non-small cell cancer and also breast cancer. However to date, there is no established test evaluating the angiogenic status of a patient and monitoring the effects of anti-angiogenic treatments. Tumor angiogenesis is the result of a balance between multiple pro- and anti¬angiogenic molecules. There is very little published clinical data exploring the impact of the anti-angiogenic therapy on the different angiogenesis-related molecules and the potential role of these molecules as prognostic or predictive factors.

Pseudoprogression after high-dose busulfan-thiotepa with autologous stem cell transplantation and radiation therapy in children with brain tumor: impact on survival

Objective: To demonstrate the incidence, time course, predisposing factor and reversibility of neurotoxicity in children with brain tumors treated with high dose busulfan-thiotepa with autologous stem cell transplantation (ASCT) and radiation therapy in our institutional experience.Materials and Methods: We performed a retrospective analysis of prospectively collected data. Between May 1988 and May 2007, 110 patients, median age 3.6 years (range, 1 months-15.3 years), with brain tumors were treated with surgical intervention and conventional chemotherapy. All patients received one course of high-dose busulfan-thiotepa with stem cell rescue, followed or preceded by radiotherapy.Results: Twenty-three patients (21%) developed neuroradiological abnormalities on follow-up imaging studies at a median time of 9.2 months (range, 5.6-17.3 months) after day 0 of ASCT. All MRI-lesions appeared in patients receiving radiotherapy after ASCT and were localized inside the 50-55 Gy isodoses. They disappeared in 14 of 23 patients with a median time of 8 months (range, 3-17 months). The presence of MRI-abnormalities was a favorable prognostic factor for overall survival on univariate analysis (hazard ratio: 0.12, 95% confidence interval [0.04, 0.33]), with a 5-year overall survival in patients with MRI-abnormalities of 84% (95% CI, 62-94), comparedto 27% (95% CI, 19-37) in those without lesions. On multivariate analysis, the presence of MRI-abnormalities was an independent prognostic factor for overall survival.Conclusion: MRI-detectable brain abnormalities are common early findings in children treated with high-dose busulfan-thiotepa followed by radiation therapy, and may mimic early tumor recurrence. They are correlated with a better outcome.

Impact of Antifibrotic Treatment on the Course of Schistosoma mansoni Infection in Murine Model

Administration of an antifibrotic agent as an adjunct to antihelmintic treatment with the objective of morbidity reduction was investigated in the murine schistosomiasis mansoni model. Antifibrotic, ß-aminopropionitrile treatment has a profound effect on the cellular matrix composition of the liver granuloma of Schistosoma mansoni infected mice when given alone, resulting in increase macrophage infiltration. These macrophages, in response to stimulation with soluble egg antigen or lipopolysaccharide produced elevated levels of nitric oxide but low levels of tumor necrosis factor alpha compared to untreated infected mice. This also correlated with reduced liver granuloma size. In spite of low numbers of eggs in the liver, mice receiving a combine treatment had a high level of resistance to a challenge infection compared with mice receiving only praziquantel. Those mice also exhibited a reduced lymphocyte proliferative response, similar to that of infected untreated mice. Antifibrotic treatment has an impact on the dynamic of the cellular nature of granulomas and impacts on the host immunity to infection

A genome-wide association study of early menopause and the combined impact of identified variants.

Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.

Simulating the Impact of Sectorial Productivity Gains on Two Regional Economies: Key Sectors from a Supply Side Perspective

In this paper we simulate and analyse the economic impact that sectorial productivity gains have on two regional Spanish economies (Catalonia and Extremadura). In particular we study the quantitative effect that each sector’s productivity gain has on household welfare (real disposable income and equivalent variation), on the consumption price indices and factor relative prices, on real production (GDP) and on the government’s net income (net taxation revenues of social transfers to households). The analytical approach consists of a computable general equilibrium model, in which we assume perfect competition and cleared markets, including factor markets. All the parameters and exogenous variables of the model are calibrated by means of two social accounting matrices, one for each region under study. The results allow us to identify those sectors with the greatest impact on consumer welfare as the key sectors in the regional economies. Keywords: Productivity gains, key sectors, computable general equilibrium

Recombinant human insulin-like growth factor I (rhIGF-I) for the treatment of amyotrophic lateral sclerosis/motor neuron disease.

BACKGROUND: Recombinant human insulin-like growth factor I (rhIGF-I) is a possible disease modifying therapy for amyotrophic lateral sclerosis (ALS, which is also known as motor neuron disease (MND)). OBJECTIVES: To examine the efficacy of rhIGF-I in affecting disease progression, impact on measures of functional health status, prolonging survival and delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival in ALS. Occurrence of adverse events was also reviewed. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (21 November 2011), CENTRAL (2011, Issue 4), MEDLINE (January 1966 to November 2011) and EMBASE (January 1980 to November 2011) and sought information from the authors of randomised clinical trials and manufacturers of rhIGF-I. SELECTION CRITERIA: We considered all randomised controlled clinical trials involving rhIGF-I treatment of adults with definite or probable ALS according to the El Escorial Criteria. The primary outcome measure was change in Appel Amyotrophic Lateral Sclerosis Rating Scale (AALSRS) total score after nine months of treatment and secondary outcome measures were change in AALSRS at 1, 2, 3, 4, 5, 6, 7, 8, 9 months, change in quality of life (Sickness Impact Profile scale), survival and adverse events. DATA COLLECTION AND ANALYSIS: Each author independently graded the risk of bias in the included studies. The lead author extracted data and the other authors checked them. We generated some missing data by making ruler measurements of data in published graphs. We collected data about adverse events from the included trials. MAIN RESULTS: We identified three randomised controlled trials (RCTs) of rhIGF-I, involving 779 participants, for inclusion in the analysis. In a European trial (183 participants) the mean difference (MD) in change in AALSRS total score after nine months was -3.30 (95% confidence interval (CI) -8.68 to 2.08). In a North American trial (266 participants), the MD after nine months was -6.00 (95% CI -10.99 to -1.01). The combined analysis from both RCTs showed a MD after nine months of -4.75 (95% CI -8.41 to -1.09), a significant difference in favour of the treated group. The secondary outcome measures showed non-significant trends favouring rhIGF-I. There was an increased risk of injection site reactions with rhIGF-I (risk ratio 1.26, 95% CI 1.04 to 1.54). . A second North American trial (330 participants) used a novel primary end point involving manual muscle strength testing. No differences were demonstrated between the treated and placebo groups in this study. All three trials were at high risk of bias. AUTHORS' CONCLUSIONS: Meta-analysis revealed a significant difference in favour of rhIGF-I treatment; however, the quality of the evidence from the two included trials was low. A third study showed no difference between treatment and placebo. There is no evidence for increase in survival with IGF1. All three included trials were at high risk of bias.

Credit risk contributions under the Vasicek one-factor model: a fast wavelet expansion approximation

To measure the contribution of individual transactions inside the total risk of a credit portfolio is a major issue in financial institutions. VaR Contributions (VaRC) and Expected Shortfall Contributions (ESC) have become two popular ways of quantifying the risks. However, the usual Monte Carlo (MC) approach is known to be a very time consuming method for computing these risk contributions. In this paper we consider the Wavelet Approximation (WA) method for Value at Risk (VaR) computation presented in [Mas10] in order to calculate the Expected Shortfall (ES) and the risk contributions under the Vasicek one-factor model framework. We decompose the VaR and the ES as a sum of sensitivities representing the marginal impact on the total portfolio risk. Moreover, we present technical improvements in the Wavelet Approximation (WA) that considerably reduce the computational effort in the approximation while, at the same time, the accuracy increases.

Statistical evaluation of the influence of writing postures on on-line signatures. Study of the impact of time.

The aim of this study is to investigate the influence of unusual writing positions on a person's signature, in comparison to a standard writing position. Ten writers were asked to sign their signature six times, in each of four different writing positions, including the standard one. In order to take into consideration the effect of the day-to-day variation, this same process was repeated over 12 sessions, giving a total of 288 signatures per subject. The signatures were collected simultaneously in an off-line and on-line acquisition mode, using an interactive tablet and a ballpoint pen. Unidimensional variables (height to width ratio; time with or without in air displacement) and time-dependent variables (pressure; X and Y coordinates; altitude and azimuth angles) were extracted from each signature. For the unidimensional variables, the position effect was assessed through ANOVA and Dunnett contrast tests. Concerning the time-dependent variables, the signatures were compared by using dynamic time warping, and the position effect was evaluated through classification by linear discriminant analysis. Both of these variables provided similar results: no general tendency regarding the position factor could be highlighted. The influence of the position factor varies according to the subject as well as the variable studied. The impact of the session factor was shown to cover the impact that could be ascribed to the writing position factor. Indeed, the day-to-day variation has a greater effect than the position factor on the studied signature variables. The results of this study suggest guidelines for best practice in the area of signature comparisons and demonstrate the importance of a signature collection procedure covering an adequate number of sampling sessions, with a sufficient number of samples per session.

Leukemic cluster growth in culture is an independent risk factor for acute myeloid leukemia and short survival in patients with myelodysplastic syndrome

In patients with myelodysplastic syndrome (MDS) precursor cell cultures (colony-forming unit cells, CFU-C) can provide an insight into the growth potential of malignant myeloid cells. In a retrospective single-center study of 73 untreated MDS patients we assessed whether CFU-C growth patterns were of prognostic value in addition to established criteria. Abnormalities were classified as qualitative (i.e. leukemic cluster growth) or quantitative (i.e. strongly reduced/absent growth). Thirty-nine patients (53%) showed leukemic growth, 26 patients (36%) had strongly reduced/absent colony growth, and 12 patients showed both. In a univariate analysis the presence of leukemic growth was associated with strongly reduced survival (at 10 years 4 vs. 34%, p = 0.004), and a high incidence of transformation to AML (76 vs. 32%, p = 0.01). Multivariate analysis identified leukemic growth as a strong and independent predictor of early death (relative risk 2.12, p = 0.03) and transformation to AML (relative risk 2.63, p = 0.04). Quantitative abnormalities had no significant impact on the disease course. CFU- C assays have significant predictive value in addition to established prognostic factors in MDS. Leukemic growth identifies a subpopulation of MDS patients with poor prognosis.

Impact of reduced cerebral perfusion pressure on outcome after severe traumatic brain injury is dependent on brain tissue oxygen pressure

INTRODUCTION. Reduced cerebral perfusion pressure (CPP) may worsen secondary damage and outcome after severe traumatic brain injury (TBI), however the optimal management of CPP is still debated. STUDY HYPOTHESIS: We hypothesized that the impact of CPP on outcome is related to brain tissue oxygen tension (PbtO2) level and that reduced CPP may worsen TBI prognosis when it is associated with brain hypoxia. DESIGN. Retrospective analysis of prospective database. METHODS. We analyzed 103 patients with severe TBI who underwent continuous PbtO2 and CPP monitoring for an average of 5 days. For each patient, duration of reduced CPP (\60 mm Hg) and brain hypoxia (PbtO2\15 mm Hg for[30 min [1]) was calculated with linear interpolation method and the relationship between CPP and PbtO2 was analyzed with Pearson's linear correlation coefficient. Outcome at 30 days was assessed with the Glasgow Outcome Score (GOS), dichotomized as good (GOS 4-5) versus poor (GOS 1-3). Multivariable associations with outcome were analyzed with stepwise forward logistic regression. RESULTS. Reduced CPP (n=790 episodes; mean duration 10.2 ± 12.3 h) was observed in 75 (74%) patients and was frequently associated with brain hypoxia (46/75; 61%). Episodes where reduced CPP were associated with normal brain oxygen did not differ significantly between patients with poor versus those with good outcome (8.2 ± 8.3 vs. 6.5 ± 9.7 h; P=0.35). In contrast, time where reduced CPP occurred simultaneously with brain hypoxia was longer in patients with poor than in those with good outcome (3.3±7.4 vs. 0.8±2.3 h; P=0.02). Outcome was significantly worse in patients who had both reduced CPP and brain hypoxia (61% had GOS 1-3 vs. 17% in those with reduced CPP but no brain hypoxia; P\0.01). Patients in whom a positive CPP-PbtO2 correlation (r[0.3) was found also were more likely to have poor outcome (69 vs. 31% in patients with no CPP-PbtO2 correlation; P\0.01). Brain hypoxia was an independent risk factor of poor prognosis (odds ratio for favorable outcome of 0.89 [95% CI 0.79-1.00] per hour spent with a PbtO2\15 mm Hg; P=0.05, adjusted for CPP, age, GCS, Marshall CT and APACHE II). CONCLUSIONS. Low CPP may significantly worsen outcome after severe TBI when it is associated with brain tissue hypoxia. PbtO2-targeted management of CPP may optimize TBI therapy and improve outcome of head-injured patients.

Vascular-endothelial-growth-factor (VEGF) targeting therapies for endocrine refractory or resistant metastatic breast cancer.

BACKGROUND: Vascular-endothelial-growth-factor (VEGF) is a key mediator of angiogenesis. VEGF-targeting therapies have shown significant benefits and been successfully integrated in routine clinical practice for other types of cancer, such as metastatic colorectal cancer. By contrast, individual trial results in metastatic breast cancer (MBC) are highly variable and their value is controversial. OBJECTIVES: To evaluate the benefits (in progression-free survival (PFS) and overall survival (OS)) and harms (toxicity) of VEGF-targeting therapies in patients with hormone-refractory or hormone-receptor negative metastatic breast cancer. SEARCH METHODS: Searches of CENTRAL, MEDLINE, EMBASE, the Cochrane Breast Cancer Group's Specialised Register, registers of ongoing trials and proceedings of conferences were conducted in January and September 2011, starting in 2000. Reference lists were scanned and members of the Cochrane Breast Cancer Group, experts and manufacturers of relevant drug were contacted to obtain further information. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials (RCTs) to evaluate treatment benefit and non-randomised studies in the routine oncology practice setting to evaluate treatment harms. DATA COLLECTION AND ANALYSIS: We performed data collection and analysis according to the published protocol. Individual patient data was sought but not provided. Therefore, the meta-analysis had to be based on published data. Summary statistics for the primary endpoint (PFS) were hazard ratios (HRs). MAIN RESULTS: We identified seven RCTs, one register, and five ongoing trials from a total of 347 references. The published trials for VEGF-targeting drugs in MBC were limited to bevacizumab. Four trials, including a total of 2886 patients, were available for the comparison of first-line chemotherapy, with versus without bevacizumab. PFS (HR 0.67; 95% confidence interval (CI) 0.61 to 0.73) and response rate were significantly better for patients treated with bevacizumab, with moderate heterogeneity regarding the magnitude of the effect on PFS. For second-line chemotherapy, a smaller, but still significant benefit in terms of PFS could be demonstrated for patients treated with bevacizumab (HR 0.85; 95% CI 0.73 to 0.98), as well as a benefit in tumour response. However, OS did not differ significantly, neither in first- (HR 0.93; 95% CI 0.84 to 1.04), nor second-line therapy (HR 0.98; 95% CI 0.83 to 1.16). Quality of life (QoL) was evaluated in four trials but results were published for only two of these with no relevant impact. Subgroup analysis stated a significant greater benefit for patients with previous (taxane) chemotherapy and patients with hormone-receptor negative status. Regarding toxicity, data from RCTs and registry data were consistent and in line with the known toxicity profile of bevacizumab. While significantly higher rates of adverse events (AEs) grade III/IV (odds ratio (OR) 1.77; 95% CI 1.44 to 2.18) and serious adverse events (SAEs) (OR 1.41; 95% CI 1.13 to 1.75) were observed in patients treated with bevacizumab, rates of treatment-related deaths were lower in patients treated with bevacizumab (OR 0.60; 95% CI 0.36 to 0.99). AUTHORS' CONCLUSIONS: The overall patient benefit from adding bevacizumab to first- and second-line chemotherapy in metastatic breast cancer can at best be considered as modest. It is dependent on the type of chemotherapy used and limited to a prolongation of PFS and response rates in both first- and second-line therapy, both surrogate parameters. In contrast, bevacizumab has no significant impact on the patient-related secondary outcomes of OS or QoL, which indicate a direct patient benefit. For this reason, the clinical value of bevacizumab for metastatic breast cancer remains controversial.

Leukemic cluster growth in culture is an independent risk factor for acute myeloid leukemia and short survival in patients with myelodysplastic syndrome.

In patients with myelodysplastic syndrome (MDS) precursor cell cultures (colony-forming unit cells, CFU-C) can provide an insight into the growth potential of malignant myeloid cells. In a retrospective single-center study of 73 untreated MDS patients we assessed whether CFU-C growth patterns were of prognostic value in addition to established criteria. Abnormalities were classified as qualitative (i.e. leukemic cluster growth) or quantitative (i.e. strongly reduced/absent growth). Thirty-nine patients (53%) showed leukemic growth, 26 patients (36%) had strongly reduced/absent colony growth, and 12 patients showed both. In a univariate analysis the presence of leukemic growth was associated with strongly reduced survival (at 10 years 4 vs. 34%, p = 0.004), and a high incidence of transformation to AML (76 vs. 32%, p = 0.01). Multivariate analysis identified leukemic growth as a strong and independent predictor of early death (relative risk 2.12, p = 0.03) and transformation to AML (relative risk 2.63, p = 0.04). Quantitative abnormalities had no significant impact on the disease course. CFU-C assays have a significant predictive value in addition to established prognostic factors in MDS. Leukemic growth identifies a subpopulation of MDS patients with poor prognosis.