BETASCAN: probable beta-amyloids identified by pairwise probabilistic analysis

Amyloids and prion proteins are clinically and biologically important beta-structures, whose supersecondary structures are difficult to determine by standard experimental or computational means. In addition, significant conformational heterogeneity is known or suspected to exist in many amyloid fibrils. Recent work has indicated the utility of pairwise probabilistic statistics in beta-structure prediction. We develop here a new strategy for beta-structure prediction, emphasizing the determination of beta-strands and pairs of beta-strands as fundamental units of beta-structure. Our program, BETASCAN, calculates likelihood scores for potential beta-strands and strand-pairs based on correlations observed in parallel beta-sheets. The program then determines the strands and pairs with the greatest local likelihood for all of the sequence's potential beta-structures. BETASCAN suggests multiple alternate folding patterns and assigns relative a priori probabilities based solely on amino acid sequence, probability tables, and pre-chosen parameters. The algorithm compares favorably with the results of previous algorithms (BETAPRO, PASTA, SALSA, TANGO, and Zyggregator) in beta-structure prediction and amyloid propensity prediction. Accurate prediction is demonstrated for experimentally determined amyloid beta-structures, for a set of known beta-aggregates, and for the parallel beta-strands of beta-helices, amyloid-like globular proteins. BETASCAN is able both to detect beta-strands with higher sensitivity and to detect the edges of beta-strands in a richly beta-like sequence. For two proteins (Abeta and Het-s), there exist multiple sets of experimental data implying contradictory structures; BETASCAN is able to detect each competing structure as a potential structure variant. The ability to correlate multiple alternate beta-structures to experiment opens the possibility of computational investigation of prion strains and structural heterogeneity of amyloid. BETASCAN is publicly accessible on the Web at http://betascan.csail.mit.edu.

Using Dynamic Analysis for API Migration

When changing the API of a framework, we need to migrate its clients. This is best done automatically. In this paper, we focus on API migration where the mechanism for inversion of control changes. We propose to use dynamic analysis for such API migration since structural refactorings alone are often not sufficient. We consider JExample as a case-study. JExample extends JUnit with first-class dependencies and fixture injection. We investigate how dynamically collected information about test coverage and about instances under test can be used to detect dependency injection candidates.

Calibration and analysis of the 2007 data

he physics program of the NA61/SHINE (SHINE = SPS Heavy Ion and Neutrino Experiment) experiment at the CERN SPS consists of three subjects. In the first stage of data taking (2007-2009) measurements of hadron production in hadron-nucleus interactions needed for neutrino (T2K) and cosmic-ray (Pierre Auger and KASCADE) experiments will be performed. In the second stage (2009-2010) hadron production in proton-proton and proton-nucleus interactions needed as reference data for a better understanding of nucleus-nucleus reactions will be studied. In the third stage (2009-2013) energy dependence of hadron production properties will be measured in p+p, p+Pb interactions and nucleus-nucleus collisions, with the aim to identify the properties of the onset of deconfinement and find evidence for the critical point of strongly interacting matter. The NA61 experiment was approved at CERN in June 2007. The first pilot run was performed during October 2007. Calibrations of all detector components have been performed successfully and preliminary uncorrected spectra have been obtained. High quality of track reconstruction and particle identification similar to NA49 has been achieved. The data and new detailed simulations confirm that the NA61 detector acceptance and particle identification capabilities cover the phase space required by the T2K experiment. This document reports on the progress made in the calibration and analysis of the 2007 data.

Impact of definitions of loss to follow-up (LTFU) in antiretroviral therapy program evaluation: variation in the definition can have an appreciable impact on estimated proportions of LTFU

OBJECTIVE To examine the impact of different definitions of loss to follow-up (LTFU) on estimates of program outcomes in cohort studies of patients on antiretroviral therapy (ART). STUDY DESIGN AND SETTING We examined the impact of different definitions of LTFU using data from the International Epidemiological Databases to Evaluate AIDS-Southern Africa. The reference approach, Definition A, was compared with five alternative scenarios that differed in eligibility for analysis and the date assigned to the LTFU outcome. Kaplan-Meier estimates of LTFU were calculated up to 2 years after starting ART. RESULTS Estimated cumulative LTFU were 14% and 22% at 12 and 24 months, respectively, using the reference approach. Differences in the proportion LTFU were reported in the alternative scenarios with 12-month estimates of LTFU varying by up to 39% compared with Definition A. Differences were largest when the date assigned to the LTFU outcome was 6 months after the date of last contact and when the site-specific definition of LTFU was used. CONCLUSION Variation in the definitions of LTFU within cohort analyses can have an appreciable impact on estimated proportions of LTFU over 2 years of follow-up. Use of a standardized definition of LTFU is needed to accurately measure program effectiveness and comparability between programs.

Ragu: a free tool for the analysis of EEG and MEG event-related scalp field data using global randomization statistics

We present a program (Ragu; Randomization Graphical User interface) for statistical analyses of multichannel event-related EEG and MEG experiments. Based on measures of scalp field differences including all sensors, and using powerful, assumption-free randomization statistics, the program yields robust, physiologically meaningful conclusions based on the entire, untransformed, and unbiased set of measurements. Ragu accommodates up to two within-subject factors and one between-subject factor with multiple levels each. Significance is computed as function of time and can be controlled for type II errors with overall analyses. Results are displayed in an intuitive visual interface that allows further exploration of the findings. A sample analysis of an ERP experiment illustrates the different possibilities offered by Ragu. The aim of Ragu is to maximize statistical power while minimizing the need for a-priori choices of models and parameters (like inverse models or sensors of interest) that interact with and bias statistics.

One-year evaluation of a neonatal screening program for cystic fibrosis in Switzerland

BACKGROUND From January 2011 onward, the Swiss newborn screening (NBS) program has included a test for cystic fibrosis (CF). In this study, we evaluate the first year of implementation of the CF-NBS program. METHODS The CF-NBS program consists of testing in two steps: a heel prick sample is drawn (= Guthrie test) for measurement of immunoreactive trypsinogen (IRT) and for DNA screening. All children with a positive screening test are referred to a CF center for further diagnostic testing (sweat test and genetic analysis). After assessment in the CF center, the parents are given a questionnaire. All the results of the screening process and the parent questionnaires were centrally collected and evaluated. RESULTS In 2011, 83 198 neonates were screened, 84 of whom (0.1%) had a positive screening result and were referred to a CF center. 30 of these 84 infants were finally diagnosed with CF (positive predictive value: 35.7%). There was an additional infant with CF and meconium ileus whose IRT value was normal. The 31 diagnosed children with CF correspond to an incidence of 1 : 2683. The average time from birth to genetically confirmed diagnosis was 34 days (range: 13-135). 91% of the parents were satisfied that their child had undergone screening. All infants receiving a diagnosis of CF went on to receive further professional care in a CF center. CONCLUSION The suggested procedure for CF-NBS has been found effective in practice; there were no major problems with its implementation. It reached high acceptance among physicians and parents.

Prognosis of Children with HIV-1 Infection Starting Antiretroviral Therapy in Southern Africa: A Collaborative Analysis of Treatment Programs

BACKGROUND: Prognostic models for children starting antiretroviral therapy (ART) in Africa are lacking. We developed models to estimate the probability of death during the first year receiving ART in Southern Africa. METHODS: We analyzed data from children ≤10 years old who started ART in Malawi, South Africa, Zambia or Zimbabwe from 2004-2010. Children lost to follow-up or transferred were excluded. The primary outcome was all-cause mortality in the first year of ART. We used Weibull survival models to construct two prognostic models: one with CD4%, age, WHO clinical stage, weight-for-age z-score (WAZ) and anemia and one without CD4%, because it is not routinely measured in many programs. We used multiple imputation to account for missing data. RESULTS: Among 12655 children, 877 (6.9%) died in the first year of ART. 1780 children were lost to follow-up/transferred and excluded from main analyses; 10875 children were included. With the CD4% model probability of death at 1 year ranged from 1.8% (95% CI: 1.5-2.3) in children 5-10 years with CD4% ≥10%, WHO stage I/II, WAZ ≥-2 and without severe anemia to 46.3% (95% CI: 38.2-55.2) in children <1 year with CD4% <5%, stage III/IV, WAZ< -3 and severe anemia. The corresponding range for the model without CD4% was 2.2% (95% CI: 1.8-2.7) to 33.4% (95% CI: 28.2-39.3). Agreement between predicted and observed mortality was good (C-statistics=0.753 and 0.745 for models with and without CD4% respectively). CONCLUSION: These models may be useful to counsel children/caregivers, for program planning and to assess program outcomes after allowing for differences in patient disease severity characteristics.

Time Preferences and Environmental Concern: An Analysis of the Swiss ISSP 2010

This study analyzes the trend of environmental concern in Switzerland using data from the International Social Survey Program (ISSP) 1993, 2000, and 2010. First, we compare the observed trend with indicators of the intensity of public debate regarding the environment. The results show that both the number of articles dealing with environmental issues in print newspapers and the debates in the Swiss parliament strongly increased during the observed period. The ecological awareness of the population, however, remained constant over this time. Second, we scrutinize the "social basis" of environmental concern paying particular attention to individuals' time preferences. Third, we investigate the relationship between environmental concern and proenvironmental behavior, on the one hand, and the relation of concern and the acceptance of governmental regulations, on the other hand.

Early development of human lymphomas in a prostate cancer xenograft program using triple knock-out immunocompromised mice

BACKGROUND There is an urgent need for preclinical models of prostate cancer; however, clinically relevant patient-derived prostate cancer xenografts (PDXs) are demanding to establish. METHODS Sixty-seven patients who were undergoing palliative transurethral surgery or radical prostatectomy for histologically confirmed, clinically relevant prostate cancer were included in the study. Fresh prostate cancer tissue was identified by frozen analysis in 48 patients. The cancer tissue was transplanted subcutaneously and under the renal capsule of NSG and NOG mice supplemented with human testosterone. All growing PDXs were evaluated by histology and immunohistochemistry. RESULTS Early assessment of the animals at least three months after transplantation included 27/48 (56.3%) eligible PDX cohorts. PDX growth was detected in 10/27 (37%) mouse cohorts. Eight of the ten PDXs were identified as human donor derived lymphomas, including seven Epstein Barr virus (EBV)-positive diffuse large B-cell lymphomas and one EBV-negative peripheral T-cell lymphoma. One sample consisted of benign prostatic tissue, and one sample comprised a benign epithelial cyst. Prostate cancer was not detected in any of the samples. CONCLUSIONS Tumors that arise within the first three months after prostate cancer xenografting may represent patient-derived EBV-positive lymphomas in up to 80% of the early growing PDXs when using triple knockout NSG immunocompromised mice. Therefore, lymphoma should be excluded in prostate cancer xenografts that do not resemble typical prostatic adenocarcinoma. Prostate 9999: XX-XX, 2014. © 2015 Wiley Periodicals, Inc.

Addressing Multilevel Program Complexity by Evaluation Design

In this paper, we present the evaluation design for a complex multilevel program recently introduced in Switzerland. The evaluation embraces the federal level, the cantonal program level, and the project level where target groups are directly addressed. We employ Pawson and Tilley’s realist evaluation approach, in order to do justice to the varying context factors that impact the cantonal programs leading to varying effectiveness of the implemented activities. The application of the model to the canton of Uri shows that the numerous vertical and horizontal relations play a crucial role for the program’s effectiveness. As a general learning for the evaluation of complex programs, we state that there is a need to consider all affected levels of a program and that no monocausal effects can be singled out in programs where multiple interventions address the same problem. Moreover, considering all affected levels of a program can mean going beyond the borders of the actual program organization and including factors that do not directly interfere with the policy delivery as such. In particular, we found that the relationship between the cantonal and the federal level was a crucial organizational factor influencing the effectiveness of the cantonal program.

Diet and mobility of an Iron Age population in Switzerland; Stable carbon, nitrogen and sulphur isotope analysis of the human remains from Münsingen

The 220 abundantly equipped burials from the Late Iron Age cemetery of Münsingen (420 – 240 BC) marked a milestone for Iron Age research. The evident horizontal spread throughout the time of occupancy laid the foundation for the chronology system of the Late Iron Age. Today the skulls of 77 individuals and some postcranial bones are still preserved. The aim was to obtain information about nutrition, social stratification and migration of the individuals from Münsingen. Stable isotope ratios of carbon, nitrogen and sulphur were analysed. The results of 63 individuals show that all consumed C3 plants as staple food with significant differences between males and females in δ13C and δ15N values. The results indicate a gender restriction in access to animal protein. Stable isotope values of one male buried with weapons and meat as grave goods suggest a diet with more animal proteins than the other individuals. It is possible that he was privileged due to high status. Furthermore, the δ34S values indicate minor mobility. Assuming that the subadults represent the local signal of δ34S it is very likely that adults with enriched δ34S could have migrated to Münsingen at some point during their lives. This study presents stable isotope values of one of the most important Late Iron Age burial sites in Central Europe. The presented data provide new insight into diet, migration and social stratification of the population from Münsingen.

Towards an analysis of tonal patterns in Amawaka, a Panoan language of Peru and Brazil

Amawaka ([ɑmɨ̃ˈwɐkɑ]) is a highly endangered and underdocumented tonal language of the Headwaters (Fleck 2011) subgroup of the Panoan family in the Southwest Amazon Basin, spoken by approximately 200 people. Undocumented phonetic and phonological phenomena of Amawaka include its tonal structure, both in terms of surface realizations and the patterns underlying these realizations. Original audiovisual data from the author’s fieldwork in various Amawaka communities at the Peru-Brazil border will illuminate the as-yet obscure tonal systematicity of the language. Unlike other elements, monosyllabic bimoraic phonological nominal words with long vowels display variation in their surface realization. All the words with the open back unrounded /ɑ/, like /ˈkɑ̀:/ (a traditional Amazonian dish), /ˈnɑ̀:/ “mestizo” etc. [with the exception of /ˈtɑ:/ “reed”, which surfaces with either a H or L tone] bear a low tone in isolation. This realization contrasts with all the encountered nominal monosyllables with vowels from the close and close-mid front and central spectrum /i, ɘ, ɨ, ɨ̃/, which clearly surface as high tone words in isolation, for example /ˈmɨ̃́:/ (a clay-lick for animals), /ˈwí:/ “Anopheles, spp. mosquito”. Monosyllables with close-mid back rounded /o/ have a less restrictive pitch that varies among speakers from low to high realizations, and sometimes even across the speech tokens from an individual speaker, e.g. /wó:/ or /wō:/ “hair”, /ɧō:/ or /ɧò:/ (a type of tarantula). Phrasal tonal phonology is more complex, when these three kinds of monosyllables appear in larger noun phrases. Some retain the same surface tones as their isolation form, while others seem to vary freely in their surface realization, e.g. /ˈtɘ́:.nɑ̀:/ or /ˈtɘ́:.nɑ́:/ ‘one mestizo’. Yet other monosyllables, e.g. /mɑ̀:/, exhibit a falling tone when preceded by a H syllable, suggesting probably latent tone sandhi phenomena, e.g /ˈtɘ́:.mɑ̂:/ (one clay-lick for parrots). In disyllabic, trisyllabic and quadrisyllabic nouns, tonal and stress patterns generally seem to be more consistent and tend to be retained both in isolation and in larger intonational phrases. Disyllabic nouns, for instance, surface as L-H or L-L when a glottal stop is in coda position. The association of L with a glottal stop is a feature that occurs in other Panoan languages as well, like Capanahua (Loos 1969), and more generally it is an areal feature, found in other parts of Amazonia (Hyman 2010). So, tone has significant interactions with the glottal stop and glottalization, which generally co-occurs with L. The data above suggest that the underlying tonal system of Amawaka is much more complex than the privative one-tone analysis (/H/ vs. Ø, i.e. lack of tone) that was proposed by Russell and Russell (1959). Evidence from field data suggests either an equipollent (Hyman 2010) two-tone opposition between /H/ and /L/, or a hybrid system, with both equipollent and privative features; that is, /H/ vs. /L/ vs. either Ø or /M/. This first systematic description of Amawaka tone, in conjunction with ongoing research, is poised to address broader questions concerning interrelationships between surface/underlying tone and other suprasegmental features, such as nasality, metrical stress, and intonation. References Fleck, David W. 2011. Panoan languages and linguistics. In Javier Ruedas and David W. Fleck (Eds.), Panoan Histories and Interethnic Identities, To appear. Hyman, Larry. 2010. Amazonia and the typology of tone systems. Presented at the conference Amazonicas III: The structure of the Amazonian languages. Bogotá. Loos, Eugene E. 1969. The phonology of Capanahua and its grammatical basis. Norman: SIL and U. Oklahoma. Russell, Robert & Dolores. 1959. Syntactotonemics in Amahuaca (Pano). Série Lingüistica Especial, 128-167. Publicaçoes do Museu Nacional, Rio de Janeiro, Brasil.

Low Risk of Death, but Substantial Program Attrition, in Pediatric HIV Treatment Cohorts in Sub-Saharan Africa

BACKGROUND: To date, an estimated 10% of children eligible for antiretroviral treatment (ART) receive it, and the frequency of retention in programs is unknown. We evaluated the 2-year risks of death and loss to follow-up (LTFU) of children after ART initiation in a multicenter study in sub-Saharan Africa. METHODS: Pooled analysis of routine individual data from 16 participating clinics produced overall Kaplan-Meier estimates of the probabilities of death or LTFU after ART initiation. Risk factors analysis used Weibull regression, accounting for between-cohort heterogeneity. RESULTS: The median age of 2405 children at ART initiation was 4.9 years (12%, younger than 12 months), 52% were male, 70% had severe immunodeficiency, and 59% started ART with a nonnucleoside reverse transcriptase inhibitor. The 2-year risk of death after ART initiation was 6.9% (95% confidence interval [CI]: 5.9 to 8.1), independently associated with baseline severe anemia (adjusted hazard ratio [aHR]: 4.10 [CI: 2.36 to 7.13]), immunodeficiency (adjusted aHR: 2.95 [CI: 1.49 to 5.82]), and severe clinical status (adjusted aHR: 3.64 [CI: 1.95 to 6.81]); the 2-year risk of LTFU was 10.3% (CI: 8.9 to 11.9), higher in children with severe clinical status. CONCLUSIONS: Once on treatment, the 2-year risk of death is low but the LTFU risk is substantial. ART is still mainly initiated at advanced disease stage in African children, reinforcing the need for early HIV diagnosis, early initiation of ART, and procedures to increase program retention.

Workshop: ASSIP - Attempted Suicide Short Intervention Program. Theory, Practice, and 24 Months Follow-up RCT.

Background: ASSIP is a manualized brief therapy based on a model of suicide as goal-directed action, aimed at establishing a therapeutic alliance in a patient-oriented, collaborative approach. The main goals of the three-session program ASSIP are for patients to understand, from an observer’s position, patterns leading to a suicidal crisis, recognize triggers and warning signs, and to establish individual safety strategies for future suicidal crises. An ongoing therapeutic support is provided with regular letters over 24 months. Method: The study was conducted in a naturalistic setting. 120 Patients were randomly assigned to an intervention group (60 participants) treated with ASSIP combined with follow-up contact through letters, and a control group (60 participants) receiving a single session of clinical assessment. Both groups had treatment as usual. Patients completed a set of psychosocial and clinical questionnaires every six months over a period of 24 months. Results: In the ASSIP group 5 patients made a total of 5 reattempts, compared to 15 patients with 41 reattempts in the control group. The survival analysis yielded a significant difference with a Wald Chi2 of .000003. The ASSIP group had significantly lower suicidal ideation and fewer days of inpatient treatment compared to the control group. Higher scores in the Penn Helping Alliance Questionnaire were associated with lower suicidal ideation during follow-up. Conclusions: ASSIP is a highly effective brief therapy for patients with recent suicide attempts. Forming a strong therapeutic alliance is considered to be a major factor for outcome. ASSIP can be used with minimal training by experienced therapists. An English version of the manual will be published in May 2015.

Biomechanical validation of computer assisted planning of periacetabular osteotomy: A preliminary study based on finite element analysis

Periacetabular Osteotomy (PAO) is a joint preserving surgical intervention intended to increase femoral head coverage and thereby to improve stability in young patients with hip dysplasia. Previously, we developed a CT-based, computer-assisted program for PAO diagnosis and planning, which allows for quantifying the 3D acetabular morphology with parameters such as acetabular version, inclination, lateral center edge (LCE) angle and femoral head coverage ratio (CO). In order to verify the hypothesis that our morphology-based planning strategy can improve biomechanical characteristics of dysplastic hips, we developed a 3D finite element model based on patient-specific geometry to predict cartilage contact stress change before and after morphology-based planning. Our experimental results demonstrated that the morphology-based planning strategy could reduce cartilage contact pressures and at the same time increase contact areas. In conclusion, our computer-assisted system is an efficient tool for PAO planning.