A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis.

BACKGROUND: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS). METHODS/PRINCIPAL FINDINGS: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95% CI: 0.71-2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated. CONCLUSION/SIGNIFICANCE: Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole. TRIAL REGISTRATION: Clinicaltrials.gov NCT00690118.

The Mont-Mort metapelites: Variscan metamorphism and geodynamic context (Brianconnais basement, Western Alps, Switzerland)

The Mont-Mort metapelites are one of the best preserved relies of the Variscan unit in the Brianconnais basement. These micaschists crystallized during a poly-phase metamorphic cycle, under amphibolite facies conditions. Mineral parageneses and geothermobarometric calculations indicate a two-stage evolution. Stage (1) (550-600 degrees C and 5-8 kbar) is documented by assemblages of zoned garnet, staurolite, kyanite(?), biotite, muscovite, quartz and pla gioclase. Stage (2) (550-600 degrees C and 2 kbar) is illustrated by assemblages of andalusite, sillimanite, muscovite, biotite. This metamorphic evolution is characterized by a nearly isothermal decompression path, terminating with the formation of andalusite-bearing veins. U-Pb monazite dates at 330 Ma and Ar-40/Ar-39 muscovite dates at 290-310 Ma (without substantial evidence of argon resetting) point to Variscan metamorphism and yield an estimate of the time interval between the thermal peak and the retrogression stage within this part of the Brianconnais basement. Restoring the Brianconnais and other Alpine basement units within an existing geodynamic model of Cordillera construction and destruction, it is possible to understand better the transition from a medium pressure/high temperature regime (collision with a peak metamorphism around 330 Ma) to low-P/high-T conditions (decompression in an extensional regime) with high geothermal gradient, as recorded by the successive Variscan parageneses within the Mont-Mort metapelites.

Capital humano local y productividad en las provincias españolas

En la última década, distintos estudios han intentado contrastar empíricamente la existencia de una relación entre el stock de capital humanolocal y la productividad del territorio, así como la posible presencia de economías externas asociadas a aquél. El resultado común de dichos estudios ha consistido en encontrar una correlación positiva entre ambas variables Losdiversos autores no coinciden, en cambio, a la hora de explicar dicho resultado: un primer grupo de autores argumenta la presencia de economíasexternas vinculadas al capital humano mientras que un segundo grupo plantea la existencia de relaciones de complementariedad entre los diversos factores productivos y, más en concreto, entre el capital humano y el capital físico.El objetivo de este trabajo es analizar la existencia de una posible relación positiva entre el nivel de capital humano de las provincias españolas y su productividad de éstas y, a continuación, averiguar si el canal a través delcual se produce el efecto son las economías externas. Para ello, se aplica unametodología que consta de dos etapas. En la primera, se estima una ecuación de Mincer utilizando información de la Encuesta de Presupuestos Familiares a fin de obtener una estimación de la productividad media de cada una de las provincias españolas una vez controlado el efecto del capital humano de los individuos sobre su propia productividad. En una segunda etapa, la estimación de la productividad provincial media estimada se introduce como variable endógena en una nueva ecuación cuyas variables explicativas intentan aproximar el nivel de capital humano de cada una de las provincias. A partir de esta segunda regresión se detecta una relación positiva entre la productividad media estimada del territorio y el nivel educativo medio delmismo. Sin embargo, la principal conclusión del análisis realizado es que dicha relación no puede explicarse por el impacto de las economías externas generadas exógenamente por el capital humano, sino que debe atribuirse a otros efectos que, actuando también por lado de la demanda, impulsen al alza la productividad.

Cetuximab In Combination With Docetaxel In Patients (Pts) With Metastatic Castration Resistant (Mcrpc) And Docetaxel-Refractory Prostate Cancer: Final Analysis Of The Multicenter Phase Ii Trial Sakk 08/07

There is no registered treatment (ttr) for pts with mCRPC who have progressive disease during or shortly after docetaxel (doc). EGFR overexpression increases in prostate cancer during the course of the disease. We investigated efficacy and safety of the combination of the monoclonal EGFR antibody cetuximab (cet) and doc in pts with mCRPC who are doc-refractory. Methods: Pts with mCRPC progressing during or < 90 days after at least 12 weeks of doc were included. Ttr consisted of the same doc regimen as prior to progression (35mg/m2 d1,8,15 q4w or 75mg/m2 q3w) in combination with cet (400mg/m2 d1, then 250mg/m2 weekly). Primary endpoint was progression free survival (PFS) at 12 weeks defined as absence of PSA progression or progression of metastases (mets). Secondary endpoints included toxicity, PFS at 24 weeks, PSA response, response of measureable disease and overall survival. 35 pts were needed in a Simon's two stage optimal design with a power of 90% and a significance level of 5% in order to test PFS rate at 12 weeks of £10% vs ?30%. Results: 35 evaluable pts were enrolled at 15 Swiss centers between 7/08 and 9/09. Median follow up was 14.8 months. Confirmed PFS at 12 weeks was 34% (95%CI 19-52%), PFS at 24 weeks was 20% and overall survival was 12.0 months (95%CI 7.1 -15.6). 20% (7/35) had a confirmed decline in PSA ? 50% and 31% (11/35) had a confirmed PSA decline ? 30%. Of pts with measurable disease (n=24) PR, SD and PD at week 12 was 4%, 54% and 25%, respectively (17% not evaluable). 3/9 (33%) pts with PDduring last doc ttr before inclusion reached the primary endpoint compared to 7/18 (39%) with PR or SD to last doc. 54% of evaluable pts experienced grade 3 and 6% grade 4 toxicity. Discussion: The result of the primary endpoint was promising in this first trial to test cet in combination with doc in pts with docetaxel-refractory mCRPC. Because this goal was achieved in such a highly pretreated pts population it appears that inhibition of the EGFR pathway may play a more important and persistent role in the treatment of prostate cancer than perceived so far. Further research is therefore warranted. Disclosure: R. Cathomas: - Membership on advisory board for sanofi aventis (suisse) and Merck. S. Gillessen: - Membership in advisory board for Sanofi Aventis. All other authors have declared no conflicts of interest.

Capital humano local y productividad en las provincias españolas

En la última década, distintos estudios han intentado contrastar empíricamente la existencia de una relación entre el stock de capital humanolocal y la productividad del territorio, así como la posible presencia de economías externas asociadas a aquél. El resultado común de dichos estudios ha consistido en encontrar una correlación positiva entre ambas variables Losdiversos autores no coinciden, en cambio, a la hora de explicar dicho resultado: un primer grupo de autores argumenta la presencia de economíasexternas vinculadas al capital humano mientras que un segundo grupo plantea la existencia de relaciones de complementariedad entre los diversos factores productivos y, más en concreto, entre el capital humano y el capital físico.El objetivo de este trabajo es analizar la existencia de una posible relación positiva entre el nivel de capital humano de las provincias españolas y su productividad de éstas y, a continuación, averiguar si el canal a través delcual se produce el efecto son las economías externas. Para ello, se aplica unametodología que consta de dos etapas. En la primera, se estima una ecuación de Mincer utilizando información de la Encuesta de Presupuestos Familiares a fin de obtener una estimación de la productividad media de cada una de las provincias españolas una vez controlado el efecto del capital humano de los individuos sobre su propia productividad. En una segunda etapa, la estimación de la productividad provincial media estimada se introduce como variable endógena en una nueva ecuación cuyas variables explicativas intentan aproximar el nivel de capital humano de cada una de las provincias. A partir de esta segunda regresión se detecta una relación positiva entre la productividad media estimada del territorio y el nivel educativo medio delmismo. Sin embargo, la principal conclusión del análisis realizado es que dicha relación no puede explicarse por el impacto de las economías externas generadas exógenamente por el capital humano, sino que debe atribuirse a otros efectos que, actuando también por lado de la demanda, impulsen al alza la productividad.

On making causal claims: A review and recommendations

Social scientists often estimate models from correlational data, where the independent variable has not been exogenously manipulated; they also make implicit or explicit causal claims based on these models. When can these claims be made? We answer this question by first discussing design and estimation conditions under which model estimates can be interpreted, using the randomized experiment as the gold standard. We show how endogeneity--which includes omitted variables, omitted selection, simultaneity, common methods bias, and measurement error--renders estimates causally uninterpretable. Second, we present methods that allow researchers to test causal claims in situations where randomization is not possible or when causal interpretation is confounded, including fixed-effects panel, sample selection, instrumental variable, regression discontinuity, and difference-in-differences models. Third, we take stock of the methodological rigor with which causal claims are being made in a social sciences discipline by reviewing a representative sample of 110 articles on leadership published in the previous 10 years in top-tier journals. Our key finding is that researchers fail to address at least 66 % and up to 90 % of design and estimation conditions that make causal claims invalid. We conclude by offering 10 suggestions on how to improve non-experimental research.

Diet and the risk of head and neck cancer: a pooled analysis in the INHANCE consortium.

We investigated the association between diet and head and neck cancer (HNC) risk using data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium. The INHANCE pooled data included 22 case-control studies with 14,520 cases and 22,737 controls. Center-specific quartiles among the controls were used for food groups, and frequencies per week were used for single food items. A dietary pattern score combining high fruit and vegetable intake and low red meat intake was created. Odds ratios (OR) and 95% confidence intervals (CI) for the dietary items on the risk of HNC were estimated with a two-stage random-effects logistic regression model. An inverse association was observed for higher-frequency intake of fruit (4th vs. 1st quartile OR = 0.52, 95% CI = 0.43-0.62, p (trend) < 0.01) and vegetables (OR = 0.66, 95% CI = 0.49-0.90, p (trend) = 0.01). Intake of red meat (OR = 1.40, 95% CI = 1.13-1.74, p p (trend) < 0.01) was positively associated with HNC risk. Higher dietary pattern scores, reflecting high fruit/vegetable and low red meat intake, were associated with reduced HNC risk (per score increment OR = 0.90, 95% CI = 0.84-0.97).

Pattern recognition ecological niche models fit to presence-only and presence-absence data

1. Identifying the boundary of a species' niche from observational and environmental data is a common problem in ecology and conservation biology and a variety of techniques have been developed or applied to model niches and predict distributions. Here, we examine the performance of some pattern-recognition methods as ecological niche models (ENMs). Particularly, one-class pattern recognition is a flexible and seldom used methodology for modelling ecological niches and distributions from presence-only data. The development of one-class methods that perform comparably to two-class methods (for presence/absence data) would remove modelling decisions about sampling pseudo-absences or background data points when absence points are unavailable. 2. We studied nine methods for one-class classification and seven methods for two-class classification (five common to both), all primarily used in pattern recognition and therefore not common in species distribution and ecological niche modelling, across a set of 106 mountain plant species for which presence-absence data was available. We assessed accuracy using standard metrics and compared trade-offs in omission and commission errors between classification groups as well as effects of prevalence and spatial autocorrelation on accuracy. 3. One-class models fit to presence-only data were comparable to two-class models fit to presence-absence data when performance was evaluated with a measure weighting omission and commission errors equally. One-class models were superior for reducing omission errors (i.e. yielding higher sensitivity), and two-classes models were superior for reducing commission errors (i.e. yielding higher specificity). For these methods, spatial autocorrelation was only influential when prevalence was low. 4. These results differ from previous efforts to evaluate alternative modelling approaches to build ENM and are particularly noteworthy because data are from exhaustively sampled populations minimizing false absence records. Accurate, transferable models of species' ecological niches and distributions are needed to advance ecological research and are crucial for effective environmental planning and conservation; the pattern-recognition approaches studied here show good potential for future modelling studies. This study also provides an introduction to promising methods for ecological modelling inherited from the pattern-recognition discipline.

Geostatistical determination of heavy-metal distribution in a contaminated site - A case study

A two stage sampling strategy is necessary in order to optimize the study of distribution of pollution in soils and groundwater. First, detailed sampling from a limited area coupled with statistical analysis of the data are used to determine the microvariability of the parameter(s). The results from this detailed analysis are then used to calculate the optimal spacing between samples for the larger scale study. This two stage sampling strategy can result in significant financial savings during subsequent soil or groundwater remediation. This combined sampling and statistical analysis approach is illustrated with an example from a heavy metal contaminated site.

Essays on the measurement of school efficiency

Measuring school efficiency is a challenging task. First, a performance measurement technique has to be selected. Within Data Envelopment Analysis (DEA), one such technique, alternative models have been developed in order to deal with environmental variables. The majority of these models lead to diverging results. Second, the choice of input and output variables to be included in the efficiency analysis is often dictated by data availability. The choice of the variables remains an issue even when data is available. As a result, the choice of technique, model and variables is probably, and ultimately, a political judgement. Multi-criteria decision analysis methods can help the decision makers to select the most suitable model. The number of selection criteria should remain parsimonious and not be oriented towards the results of the models in order to avoid opportunistic behaviour. The selection criteria should also be backed by the literature or by an expert group. Once the most suitable model is identified, the principle of permanence of methods should be applied in order to avoid a change of practices over time. Within DEA, the two-stage model developed by Ray (1991) is the most convincing model which allows for an environmental adjustment. In this model, an efficiency analysis is conducted with DEA followed by an econometric analysis to explain the efficiency scores. An environmental variable of particular interest, tested in this thesis, consists of the fact that operations are held, for certain schools, on multiple sites. Results show that the fact of being located on more than one site has a negative influence on efficiency. A likely way to solve this negative influence would consist of improving the use of ICT in school management and teaching. Planning new schools should also consider the advantages of being located on a unique site, which allows reaching a critical size in terms of pupils and teachers. The fact that underprivileged pupils perform worse than privileged pupils has been public knowledge since Coleman et al. (1966). As a result, underprivileged pupils have a negative influence on school efficiency. This is confirmed by this thesis for the first time in Switzerland. Several countries have developed priority education policies in order to compensate for the negative impact of disadvantaged socioeconomic status on school performance. These policies have failed. As a result, other actions need to be taken. In order to define these actions, one has to identify the social-class differences which explain why disadvantaged children underperform. Childrearing and literary practices, health characteristics, housing stability and economic security influence pupil achievement. Rather than allocating more resources to schools, policymakers should therefore focus on related social policies. For instance, they could define pre-school, family, health, housing and benefits policies in order to improve the conditions for disadvantaged children.

Failure of surgical treatment in 115 infected total hip arthroplasties - analysis of a 12-year prosthetic joint cohort study (1999-2010)

Infection of total hip arthroplasties (THA) leads to significant long-termmorbidity and high healthcare costs. We evaluated the differentreasons for treatment failure using different surgical modalities in a12-year prosthetic joint infection cohort study.Method: All patients hospitalized at our institution with infected THAwere included either retrospectively (1999-2007) or prospectively(2008-2010). THA infection was defined as growth of the same microorganismin ≥2 tissue or synovial fluid culture, visible purulence, sinustract or acute inflammation on tissue histopathology. Outcome analysiswas performed at outpatient visits, followed by contacting patients,their relatives and/or treating physicians afterwards.Results: During the study period, 117 patients with THA were identified.We exclude 2 patients due to missing data. The median age was69 years (range, 33-102 years); 42% were women. THA was mainlyperformed for osteoarthritis (n = 84), followed by trauma (n = 22),necrosis (n = 4), dysplasia (n = 2), rheumatoid arthritis (n = 1), osteosarcoma(n = 1) and tuberculosis (n = 1). 28 infections occurred early(≤3 months), 25 delayed (3-24 months) and 63 late (≥24 months aftersurgery). Infected THA were treated with (i) two-stage exchange in59 patients (51%, cure rate: 93%), (ii) one-stage exchange in 5 (4.3%,cure rate: 100%), (iii) debridement with change of mobile parts in18 (17%, cure rate: 83%), (iv) debridement without change of mobileparts in 17 (14%, cure rate: 53% ), (v) Girdlestone in 13 (11%, curerate: 100%), and (vi) two-stage exchange followed by removal in 3(2.6%). Patients were followed for a mean of 3.9 years (range, 0.1 to 9years), 7 patients died unrelated to the infected THA. 15 patients (13%)needed additional operations, 1 for mechanical reasons (dislocationof spacer) and 14 for persistent infection: 11 treated with debridementand retention (8 without change and 3 with change of mobile parts)and 3 with two-stage exchange. The mean number of surgery was 2.2(range, 1 to 5). The infection was finally eradicated in all patients, butthe functional outcome remained unsatisfactory in 20% (persistentpain or impaired mobility due to spacer or Girdlestone situation).Conclusions: Non-respect of current treatment concept leads totreatment failure with subsequent operations. Precise analysis of eachtreatment failures can be used for improving the treatment algorithmleading to better results.

Iowa Power Fund Board Project Report Update, July 29, 2009

Amana Farms is using an anaerobic digestion, which is a two-stage digester that converts manure and other organic wastes into three valuable by-products: 1) Biogas – to fuel an engine/generator set to create electricity; 2) Biosolids - used as a livestock bedding material or as a soil amendment; 3) Liquid stream - will be applied as a low-odor fertilizer to growing crops. (see Business Plan appendix H) The methane biogas will be collected from the two stages of the anaerobic digestion vessel and used for fuel in the combined heat and power engine/generator sets. The engine/generator sets are natural gasfueled reciprocating engines modified to burn biogas. The electricity produced by the engine/generator sets will be used to offset on-farm power consumption and the excess power will be sold directly to Amana Society Service Company as a source of green power. The waste heat, in the form of hot water, will be collected from both the engine jacket liquid cooling system and from the engine exhaust (air) system. Approximately 30 to 60% of this waste heat will be used to heat the digester. The remaining waste heat will be used to heat other farm buildings and may provide heat for future use for drying corn or biosolids. The digester effluent will be pumped from the effluent pit at the end of the anaerobic digestion vessel to a manure solids separator. The mechanical manure separator will separate the effluent digested waste stream into solid and liquid fractions. The solids will be dewatered to approximately a 35% solid material. Some of the separated solids will be used by the farm for a livestock bedding replacement. The remaining separated solids may be sold to other farms for livestock bedding purposes or sold to after-markets, such as nurseries and composters for soil amendment material. The liquid from the manure separator, now with the majority of the large solids removed, will be pumped into the farm’s storage lagoon. A significant advantage of the effluent from the anaerobic digestion treatment process is that the viscosity of the effluent is such that the liquid effluent can now be pumped through an irrigation nozzle for field spreading.

Large-scale clustering through functional embedding

We present a new framework for large-scale data clustering. The main idea is to modify functional dimensionality reduction techniques to directly optimize over discrete labels using stochastic gradient descent. Compared to methods like spectral clustering our approach solves a single optimization problem, rather than an ad-hoc two-stage optimization approach, does not require a matrix inversion, can easily encode prior knowledge in the set of implementable functions, and does not have an ?out-of-sample? problem. Experimental results on both artificial and real-world datasets show the usefulness of our approach.

Simple holographic polarogram

A new technique capable of obtaining quantitative values of the rotation angle of the polarization vector by using holography is presented. This is a two-stage holographic process; during the recording stage a hologram of the object of interest is obtained. The reference beam is composed of two beams that form a small angle between them and keep their polarization states at right angles to each other. In the reconstruction stage of the hologram, two images from the hologram are obtained along two different angles. As a result of the interference between these two images, a set of parallel fringes is formed at the image plane. The fringe contrast on the reconstruction is related to the angle of the polarization vector of the light at each position on the image plane. Measurements of the rotation of the polarization angle of a fraction of a degree were obtained. The main application of this technique is in the study of transient phenomena, where single-shot measurements are the only means of obtaining reliable data.

What treatment for periprosthetic shoulder infection? Results from a multicentre retrospective series.

PURPOSE: Controversy still exists as to the best surgical treatment for periprosthetic shoulder infections. The aim of this multi-institutional study was to review a continuous retrospective series of patients treated in four European centres and to assess the respective eradication rate of various treatment approaches. METHODS: Forty-four patients were available for this retrospective follow-up evaluation. Functional and clinical evaluation of treatment for infection was performed using the Constant-Murley score, visual analogue scale and patient satisfaction Neer score. Erythrocyte sedimentation rate, serum leucocyte count and C-reactive protein were measured and shoulder X-ray examination performed prior to surgery and at the latest follow-up. RESULTS: At a mean follow-up of 41 months (range 24-98), 42 of 44 patients (95.5%) showed no signs of infection recurrence/persistence. Comparable eradication rates were observed after resection arthroplasty (100%; 6/6), two-stage revision (17/17) or permanent antibiotic-loaded spacer implant (93.3%; 14/15). No patient was treated by one-stage revision. On average, both functional and pain scores improved significantly; the worst joint function was observed after resection arthroplasty. CONCLUSIONS: This retrospective analysis conducted on the largest published series of patients to date shows comparable infection eradication rates after two-stage revision, resection arthroplasty or permanent spacer implant for the treatment of septic shoulder prosthesis.