Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson's disease.

ObjectiveTo understand the safety, putaminal coverage, and enzyme expression of adeno-associated viral vector serotype-2 encoding the complementary DNA for the enzyme, aromatic L-amino acid decarboxylase (VY-AADC01), delivered using novel intraoperative monitoring to optimize delivery.MethodsFifteen subjects (three cohorts of 5) with moderately advanced Parkinson's disease and medically refractory motor fluctuations received VY-AADC01 bilaterally coadministered with gadoteridol to the putamen using intraoperative magnetic resonance imaging (MRI) guidance to visualize the anatomic spread of the infusate and calculate coverage. Cohort 1 received 8.3 × 1011 vg/ml and ≤450 μl per putamen (total dose, ≤7.5 × 1011 vg); cohort 2 received the same concentration (8.3 × 1011 vg/ml) and ≤900 μl per putamen (total dose, ≤1.5 × 1012 vg); and cohort 3 received 2.6 × 1012 vg/ml and ≤900 μl per putamen (total dose, ≤4.7 × 1012 vg). (18)F-fluoro-L-dihydroxyphenylalanine positron emission tomography (PET) at baseline and 6 months postprocedure assessed enzyme activity; standard assessments measured clinical outcomes.ResultsMRI-guided administration of ascending VY-AADC01 doses resulted in putaminal coverage of 21% (cohort 1), 34% (cohort 2), and 42% (cohort 3). Cohorts 1, 2, and 3 showed corresponding increases in enzyme activity assessed by PET of 13%, 56%, and 79%, and reductions in antiparkinsonian medication of -15%, -33%, and -42%, respectively, at 6 months. At 12 months, there were dose-related improvements in clinical outcomes, including increases in patient-reported ON-time without troublesome dyskinesia (1.6, 3.3, and 1.5 hours, respectively) and quality of life.InterpretationNovel intraoperative monitoring of administration facilitated targeted delivery of VY-AADC01 in this phase 1 study, which was well tolerated. Increases in enzyme expression and clinical improvements were dose dependent. ClinicalTrials.gov Identifier: NCT01973543 Ann Neurol 2019;85:704-714

Quasi-Elastic Scattering in the Inclusive (3^3He, t) Reaction

The triton energy spectra of the charge-exchange $^{12}$C($^3$He,t) reaction at 2 GeV beam energy are analyzed in the quasi-elastic nucleon knock-out region. Considering that this region is mainly populated by the charge-exchange of a proton in $^3$He with a neutron in the target nucleus and the final proton going in the continuum, the cross-sections are written in the distorted-wave impulse approximation. The t-matrix for the elementary exchange process is constructed in the DWBA, using one pion- plus rho-exchange potential for the spin-isospin nucleon- nucleon potential. This t-matrix reproduces the experimental data on the elementary pn $\rightarrow$np process. The calculated cross-sections for the $^{12}$C($^3$He,t) reaction at $2^o$ to $7^o$ triton emission angle are compared with the corresponding experimental data, and are found in reasonable overall accord.Comment: 19 pages, latex, 11 postscript figures available at [email protected], submitted to Phy.Rev.

Consistent off-shell πNN\pi N N vertex and nucleon self-energy

We present a consistent calculation of half-off-shell form factors in the pion-nucleon vertex and the nucleon self-energy. Numerical results are presented. Near the on-shell point the pion-nucleon vertex is dominated by the pseudovector coupling, while at large nucleon invariant masses we find a sizable pseudoscalar admixture.Comment: 23 pages, 7 figures, REVTeX, submitted to Phys. Rev. C, replaced with corrected versio

PU.1 controls fibroblast polarization and tissue fibrosis

Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix, which induces scarring and organ failure. By contrast, a hallmark feature of fibroblasts in arthritis is degradation of the extracellular matrix because of the release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms that drive these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts remain unknown. Here we identify the transcription factor PU.1 as an essential regulator of the pro-fibrotic gene expression program. The interplay between transcriptional and post-transcriptional mechanisms that normally control the expression of PU.1 expression is perturbed in various fibrotic diseases, resulting in the upregulation of PU.1, induction of fibrosis-associated gene sets and a phenotypic switch in extracellular matrix-producing pro-fibrotic fibroblasts. By contrast, pharmacological and genetic inactivation of PU.1 disrupts the fibrotic network and enables reprogramming of fibrotic fibroblasts into resting fibroblasts, leading to regression of fibrosis in several organs

Children's Medicines in Tanzania: A National Survey of Administration Practices and Preferences.

The dearth of age-appropriate formulations of many medicines for children poses a major challenge to pediatric therapeutic practice, adherence, and health care delivery worldwide. We provide information on current administration practices of pediatric medicines and describe key stakeholder preferences for new formulation characteristics. We surveyed children aged 6-12 years, parents/caregivers over age 18 with children under age 12, and healthcare workers in 10 regions of Tanzania to determine current pediatric medicine prescription and administration practices as well as preferences for new formulations. Analyses were stratified by setting, pediatric age group, parent/caregiver education, and healthcare worker cadre. Complete data were available for 206 children, 202 parents/caregivers, and 202 healthcare workers. Swallowing oral solid dosage forms whole or crushing/dissolving them and mixing with water were the two most frequently reported methods of administration. Children frequently reported disliking medication taste, and many had vomited doses. Healthcare workers reported medicine availability most significantly influences prescribing practices. Most parents/caregivers and children prefer sweet-tasting medicine. Parents/caregivers and healthcare workers prefer oral liquid dosage forms for young children, and had similar thresholds for the maximum number of oral solid dosage forms children at different ages can take. There are many impediments to acceptable and accurate administration of medicines to children. Current practices are associated with poor tolerability and the potential for under- or over-dosing. Children, parents/caregivers, and healthcare workers in Tanzania have clear preferences for tastes and formulations, which should inform the development, manufacturing, and marketing of pediatric medications for resource-limited settings

The University of Akron Human Powered Vehicle Team

The University of Akron Human Powered Vehicle Team’s 2016 vehicle, Klokan, was designed, manufactured and tested with safety, reliability, performance and ease of use in mind. The vehicle is a fully faired tadpole trike with a lightweight aluminum frame constructed from 6061-T6 tubing having a total weight of 8.9 lbs. To complement the lightweight frame, the fairing is constructed from polycarbonate, PETG and carbon fiber strips which combine into a lightweight, easy to manufacture weather barrier and aerodynamic structure. Klokan was designed to be a safe and efficient mode of everyday transportation which ensures that riders are sufficiently protected by a rollover protection system (RPS) which was designed to meet the ASME HPVC requirements with a minimum safety factor of two. The project scope includes all aspects of design and fabrication to create a vehicle that is easy to manufacture, easy to use, safe, and low cost to facilitate its usability in everyday situations. The team completed research on how to improve the manufacturability, reliability, and performance through analysis of designs, computer based modeling, and physical testing to validate that the bike meets team goals as well as exceeding the requirements set by the ASME Human Powered Vehicle Competition. The frame was designed in a manner that reduces welding through the use of bends and allows for precision fixturing to be manufactured and used to construct multiple frames quickly and efficiently. The fairing’s modular construction reduces the need for specialized tooling while minimizing weight and construction time. The team designed and successfully implemented an innovative rollover warning system which actively monitors the percentage of vehicle load on each tire and warns the driver through audible tone and visual warning light prior to a dangerous rollover becoming imminent

A Finite Representation of the Narrowing Space

The final publication is available at Springer via http://dx.doi.org/10.1007/978-3-319-14125-1_4Narrowing basically extends rewriting by allowing free variables in terms and by replacing matching with unification. As a consequence, the search space of narrowing becomes usually infinite, as in logic programming. In this paper, we introduce the use of some operators that allow one to always produce a finite data structure that still represents all the narrowing derivations. Furthermore, we extract from this data structure a novel, compact equational representation of the (possibly infinite) answers computed by narrowing for a given initial term. Both the finite data structure and the equational representation of the computed answers might be useful in a number of areas, like program comprehension, static analysis, program transformation, etc.Nishida, N.; Vidal, G. (2013). A Finite Representation of the Narrowing Space. En Logic-Based Program Synthesis and Transformation. Springer. 54-71. doi:10.1007/978-3-319-14125-1_4S5471Albert, E., Vidal, G.: The Narrowing-Driven Approach to Functional Logic Program Specialization. New Generation Computing 20(1), 3–26 (2002)Alpuente, M., Falaschi, M., Vidal, G.: Partial Evaluation of Functional Logic Programs. ACM Transactions on Programming Languages and Systems 20(4), 768–844 (1998)Alpuente, M., Falaschi, M., Vidal, G.: Compositional Analysis for Equational Horn Programs. In: Rodríguez-Artalejo, M., Levi, G. (eds.) ALP 1994. LNCS, vol. 850, pp. 77–94. Springer, Heidelberg (1994)Antoy, S., Ariola, Z.: Narrowing the Narrowing Space. In: Hartel, P.H., Kuchen, H. (eds.) PLILP 1997. LNCS, vol. 1292, pp. 1–15. Springer, Heidelberg (1997)Arts, T., Giesl, J.: Termination of term rewriting using dependency pairs. Theoretical Computer Science 236(1–2), 133–178 (2000)Arts, T., Zantema, H.: Termination of Logic Programs Using Semantic Unification. In: Proietti, M. (ed.) LOPSTR 1995. LNCS, vol. 1048, pp. 219–233. Springer, Heidelberg (1996)Baader, F., Nipkow, T.: Term Rewriting and All That. Cambridge University Press (1998)Bae, K., Escobar, S., Meseguer, J.: Abstract Logical Model Checking of Infinite-State Systems Using Narrowing. In: Proceedings of the 24th International Conference on Rewriting Techniques and Applications. LIPIcs, vol. 21, pp. 81–96. Schloss Dagstuhl - Leibniz-Zentrum für Informatik (2013)De Schreye, D., Glück, R., Jørgensen, J., Leuschel, M., Martens, B., Sørensen, M.: Conjunctive partial deduction: foundations, control, algorihtms, and experiments. Journal of Logic Programming 41(2&3), 231–277 (1999)Escobar, S., Meadows, C., Meseguer, J.: A rewriting-based inference system for the NRL Protocol Analyzer and its meta-logical properties. Theoretical Computer Science 367(1–2), 162–202 (2006)Escobar, S., Meseguer, J.: Symbolic Model Checking of Infinite-State Systems Using Narrowing. In: Baader, F. (ed.) RTA 2007. LNCS, vol. 4533, pp. 153–168. Springer, Heidelberg (2007)Fribourg, L.: SLOG: A Logic Programming Language Interpreter Based on Clausal Superposition and Rewriting. In: Proceedings of the Symposium on Logic Programming, pp. 172–185. IEEE Press (1985)Gnaedig, I., Kirchner, H.: Proving weak properties of rewriting. Theoretical Computer Science 412(34), 4405–4438 (2011)Hanus, M.: The integration of functions into logic programming: From theory to practice. Journal of Logic Programming 19&20, 583–628 (1994)Hanus, M. (ed.): Curry: An integrated functional logic language (vers. 0.8.3) (2012). http://www.curry-language.orgHermenegildo, M., Rossi, F.: On the Correctness and Efficiency of Independent And-Parallelism in Logic Programs. In: Lusk, E., Overbeck, R. (eds.) Proceedings of the 1989 North American Conf. on Logic Programming, pp. 369–389. The MIT Press, Cambridge (1989)Hölldobler, S. (ed.): Foundations of Equational Logic Programming. LNCS, vol. 353. Springer, Heidelberg (1989)Meseguer, J., Thati, P.: Symbolic Reachability Analysis Using Narrowing and its Application to Verification of Cryptographic Protocols. Electronic Notes in Theoretical Computer Science 117, 153–182 (2005)Middeldorp, A., Okui, S.: A Deterministic Lazy Narrowing Calculus. Journal of Symbolic Computation 25(6), 733–757 (1998)Nishida, N., Sakai, M., Sakabe, T.: Generation of Inverse Computation Programs of Constructor Term Rewriting Systems. IEICE Transactions on Information and Systems J88–D–I(8), 1171–1183 (2005) (in Japanese)Nishida, N., Sakai, M., Sakabe, T.: Partial Inversion of Constructor Term Rewriting Systems. In: Giesl, J. (ed.) RTA 2005. LNCS, vol. 3467, pp. 264–278. Springer, Heidelberg (2005)Nishida, N., Vidal, G.: Program inversion for tail recursive functions. In: Schmidt-Schauß, M. (ed.) Proceedings of the 22nd International Conference on Rewriting Techniques and Applications. LIPIcs, vol. 10, pp. 283–298. Schloss Dagstuhl - Leibniz-Zentrum für Informatik (2011)Nishida, N., Vidal, G.: Computing More Specific Versions of Conditional Rewriting Systems. In: Albert, E. (ed.) LOPSTR 2012. LNCS, vol. 7844, pp. 137–154. Springer, Heidelberg (2013)Nutt, W., Réty, P., Smolka, G.: Basic Narrowing Revisited. Journal of Symbolic Computation 7(3/4), 295–317 (1989)Ohlebusch, E.: Advanced Topics in Term Rewriting. Springer, London, UK (2002)Palamidessi, C.: Algebraic Properties of Idempotent Substitutions. In: Paterson, M. (ed.) ICALP 1990. LNCS, vol. 443, pp. 386–399. Springer, Heidelberg (1990)Ramos, J.G., Silva, J., Vidal, G.: Fast Narrowing-Driven Partial Evaluation for Inductively Sequential Systems. In: Danvy, O., Pierce, B.C. (eds.) Proceedings of the 10th ACM SIGPLAN International Conference on Functional Programming, pp. 228–239. ACM Press (2005)Slagle, J.R.: Automated theorem-proving for theories with simplifiers, commutativity and associativity. Journal of the ACM 21(4), 622–642 (1974

Global access to surgical care: a modelling study

Background More than 2 billion people are unable to receive surgical care based on operating theatre density alone. The vision of the Lancet Commission on Global Surgery is universal access to safe, aff ordable surgical and anaesthesia care when needed. We aimed to estimate the number of individuals worldwide without access to surgical services as defi ned by the Commission’s vision. Methods We modelled access to surgical services in 196 countries with respect to four dimensions: timeliness, surgical capacity, safety, and aff ordability. We built a chance tree for each country to model the probability of surgical access with respect to each dimension, and from this we constructed a statistical model to estimate the proportion of the population in each country that does not have access to surgical services. We accounted for uncertainty with oneway sensitivity analyses, multiple imputation for missing data, and probabilistic sensitivity analysis. Findings At least 4·8 billion people (95% posterior credible interval 4·6–5·0 [67%, 64–70]) of the world’s population do not have access to surgery. The proportion of the population without access varied widely when stratifi ed by epidemiological region: greater than 95% of the population in south Asia and central, eastern, and western sub- Saharan Africa do not have access to care, whereas less than 5% of the population in Australasia, high-income North America, and western Europe lack access. Interpretation Most of the world’s population does not have access to surgical care, and access is inequitably distributed. The near absence of access in many low-income and middle-income countries represents a crisis, and as the global health community continues to support the advancement of universal health coverage, increasing access to surgical services will play a central role in ensuring health care for all

Medical decision making for patients with Parkinson disease under Average Cost Criterion

Parkinson's disease (PD) is one of the most common disabling neurological disorders and results in substantial burden for patients, their families and the as a whole society in terms of increased health resource use and poor quality of life. For all stages of PD, medication therapy is the preferred medical treatment. The failure of medical regimes to prevent disease progression and to prevent long-term side effects has led to a resurgence of interest in surgical procedures. Partially observable Markov decision models (POMDPs) are a powerful and appropriate technique for decision making. In this paper we applied the model of POMDP's as a supportive tool to clinical decisions for the treatment of patients with Parkinson's disease. The aim of the model was to determine the critical threshold level to perform the surgery in order to minimize the total lifetime costs over a patient's lifetime (where the costs incorporate duration of life, quality of life, and monetary units). Under some reasonable conditions reflecting the practical meaning of the deterioration and based on the various diagnostic observations we find an optimal average cost policy for patients with PD with three deterioration levels