Hybrid Equation/Agent-Based Model of Ischemia-Induced Hyperemia and Pressure Ulcer Formation Predicts Greater Propensity to Ulcerate in Subjects with Spinal Cord Injury

Pressure ulcers are costly and life-threatening complications for people with spinal cord injury (SCI). People with SCI also exhibit differential blood flow properties in non-ulcerated skin. We hypothesized that a computer simulation of the pressure ulcer formation process, informed by data regarding skin blood flow and reactive hyperemia in response to pressure, could provide insights into the pathogenesis and effective treatment of post-SCI pressure ulcers. Agent-Based Models (ABM) are useful in settings such as pressure ulcers, in which spatial realism is important. Ordinary Differential Equation-based (ODE) models are useful when modeling physiological phenomena such as reactive hyperemia. Accordingly, we constructed a hybrid model that combines ODEs related to blood flow along with an ABM of skin injury, inflammation, and ulcer formation. The relationship between pressure and the course of ulcer formation, as well as several other important characteristic patterns of pressure ulcer formation, was demonstrated in this model. The ODE portion of this model was calibrated to data related to blood flow following experimental pressure responses in non-injured human subjects or to data from people with SCI. This model predicted a higher propensity to form ulcers in response to pressure in people with SCI vs. non-injured control subjects, and thus may serve as novel diagnostic platform for post-SCI ulcer formation. © 2013 Solovyev et al

Contingency management to reduce methamphetamine use and sexual risk among men who have sex with men: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Methamphetamine use is associated with HIV acquisition and transmission among men who have sex with men (MSM). Contingency management (CM), providing positive reinforcement for drug abstinence and withholding reinforcement when abstinence is not demonstrated, may facilitate reduced methamphetamine use and sexual risk. We compared CM as a stand-alone intervention to a minimal intervention control to assess the feasibility of conducting a larger, more definitive trial of CM; to define the frequency of behavioral outcomes to power such a trial; and, to compute preliminary estimates of CM's effectiveness.</p> <p>Methods</p> <p>We randomly assigned 127 MSM from Seattle, WA who use methamphetamine to receive a 12-week CM intervention (n = 70) or referral to community resources (n = 57).</p> <p>Results</p> <p>Retention at 24 weeks was 84%. Comparing consecutive study visits, non-concordant UAI declined significantly in both study arms. During the intervention, CM and control participants were comparably likely to provide urine samples containing methamphetamine (adjusted relative risk [aRR] = 1.09; 95%CI: 0.71, 1.56) and to report non-concordant UAI (aRR = 0.80; 95%CI: 0.47, 1.35). However, during post-intervention follow-up, CM participants were somewhat more likely to provide urine samples containing methamphetamine than control participants (aRR = 1.21; 95%CI: 0.95, 1.54, <it>P </it>= 0.11). Compared to control participants, CM participants were significantly more likely to report weekly or more frequent methamphetamine use and use of more than eight quarters of methamphetamine during the intervention and post-intervention periods.</p> <p>Conclusions</p> <p>While it is possible to enroll and retain MSM who use methamphetamine in a trial of CM conducted outside drug treatment, our data suggest that CM is not likely to have a large, sustained effect on methamphetamine use.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier <b>NCT01174654</b></p

Rapid Analysis of Vessel Elements (RAVE): A Tool for Studying Physiologic, Pathologic and Tumor Angiogenesis

Quantification of microvascular network structure is important in a myriad of emerging research fields including microvessel remodeling in response to ischemia and drug therapy, tumor angiogenesis, and retinopathy. To mitigate analyst-specific variation in measurements and to ensure that measurements represent actual changes in vessel network structure and morphology, a reliable and automatic tool for quantifying microvascular network architecture is needed. Moreover, an analysis tool capable of acquiring and processing large data sets will facilitate advanced computational analysis and simulation of microvascular growth and remodeling processes and enable more high throughput discovery. To this end, we have produced an automatic and rapid vessel detection and quantification system using a MATLAB graphical user interface (GUI) that vastly reduces time spent on analysis and greatly increases repeatability. Analysis yields numerical measures of vessel volume fraction, vessel length density, fractal dimension (a measure of tortuosity), and radii of murine vascular networks. Because our GUI is open sourced to all, it can be easily modified to measure parameters such as percent coverage of non-endothelial cells, number of loops in a vascular bed, amount of perfusion and two-dimensional branch angle. Importantly, the GUI is compatible with standard fluorescent staining and imaging protocols, but also has utility analyzing brightfield vascular images, obtained, for example, in dorsal skinfold chambers. A manually measured image can be typically completed in 20 minutes to 1 hour. In stark comparison, using our GUI, image analysis time is reduced to around 1 minute. This drastic reduction in analysis time coupled with increased repeatability makes this tool valuable for all vessel research especially those requiring rapid and reproducible results, such as anti-angiogenic drug screening

High order structure preserving explicit methods for solving linear-quadratic optimal control problems

[EN] We consider the numerical integration of linear-quadratic optimal control problems. This problem requires the solution of a boundary value problem: a non-autonomous matrix Riccati differential equation (RDE) with final conditions coupled with the state vector equation with initial conditions. The RDE has positive definite matrix solution and to numerically preserve this qualitative property we propose first to integrate this equation backward in time with a sufficiently accurate scheme. Then, this problem turns into an initial value problem, and we analyse splitting and Magnus integrators for the forward time integration which preserve the positive definite matrix solutions for the RDE. Duplicating the time as two new coordinates and using appropriate splitting methods, high order methods preserving the desired property can be obtained. The schemes make sequential computations and do not require the storrage of intermediate results, so the storage requirements are minimal. The proposed methods are also adapted for solving linear-quadratic N-player differential games. The performance of the splitting methods can be considerably improved if the system is a perturbation of an exactly solvable problem and the system is properly split. Some numerical examples illustrate the performance of the proposed methods.The author wishes to thank the University of California San Diego for its hospitality where part of this work was done. He also acknowledges the support of the Ministerio de Ciencia e Innovacion (Spain) under the coordinated project MTM2010-18246-C03. The author also acknowledges the suggestions by the referees to improve the presentation of this work.Blanes Zamora, S. (2015). High order structure preserving explicit methods for solving linear-quadratic optimal control problems. Numerical Algorithms. 69:271-290. https://doi.org/10.1007/s11075-014-9894-0S27129069Abou-Kandil, H., Freiling, G., Ionescy, V., Jank, G.: Matrix Riccati equations in control and systems theory. Basel, Burkhäuser Verlag (2003)Al-Mohy, A.H., Higham, N.J.: Computing the Action of the Matrix Exponential, with an Application to Exponential Integrators. SIAM. J. Sci. Comp. 33, 488–511 (2011)Anderson, B.D.O., Moore, J.B.: Optimal control: linear quadratic methods. Dover, New York (1990)Ascher, U.M., Mattheij, R.M., Russell, R.D.: Numerical solutions of boundary value problems for ordinary differential equations. Prentice-Hall, Englewood Cliffs (1988)Bader, P., Blanes, S., Ponsoda, E.: Structure preserving integrators for solving linear quadratic optimal control problems with applications to describe the flight of a quadrotor. J. Comput. Appl. Math. 262, 223–233 (2014)Basar, T., Olsder, G.J.: Dynamic non cooperative game theory, 2nd Ed, SIAM, Philadelphhia (1999)Blanes, S., Casas, F.: On the necessity of negative coefficients for operator splitting schemes of order higher than two. Appl. Num. Math. 54, 23–37 (2005)Blanes, S., Casas, F., Farrés, A., Laskar, J., Makazaga, J., Murua, A.: New families of symplectic splitting methods for numerical integration in dynamical astronomy. Appl. Numer. Math. 68, 58–72 (2013)Blanes, S., Casas, F., Oteo, J.A., Ros, J.: The Magnus expansion and some of its applications. Phys. Rep. 470, 151–238 (2009)Blanes, S., Casas, F., Ros, J.: High order optimized geometric integrators for linear differential equations. BIT 42, 262–284 (2002)Blanes, S., Diele, F., Marangi, C., Ragni, S.: Splitting and composition methods for explicit time dependence in separable dynamical systems. J. Comput. Appl. Math. 235, 646–659 (2010)Blanes, S., Moan, P.C.: Practical symplectic partitioned Runge-Kutta and Runge-Kutta-Nystrm methods. J. Comput. Appl. Math. 142, 313–330 (2002)Blanes, S., Ponsoda, E.: Magnus integrators for solving linear-quadratic differential games. J. Comput. Appl. Math. 236, 3394–3408 (2012)Brif, C., Chakrabarti, R., Rabitz, H.: Control of quantum phenomena: past, present and future. New J. Phys. 12, 075008(68pp) (2010)Cruz, J.B., Chen, C.I.: Series Nash solution of two person non zero sum linear quadratic games. J. Optim. Theory Appl. 7, 240–257 (1971)Dieci, L., Eirola, T.: Positive definitness in the numerical solution of Riccati differential quations. Numer. Math. 67, 303–313 (1994)Engwerda, J.: LQ dynamic optimization and differential games. Wiley (2005)Hairer, E., Lubich, C., Wanner, G.: Geometric Numerical Integration. Structure-Preserving Algorithms for Ordinary Differential Equations (2nd edition). Springer Series in Computational Mathematics, 31. Springer-Verlag (2006)Hochbruck, M., Ostermann, A.: Exponential integrators. Acta Numerica 19, 209–286 (2010)Horn, R.A., Johnson, C.R.: Matrix Analysis. Cambridge University Press, New York (1985)Iserles, A., Munthe-Kaas, H.Z., Nørsett, S.P., Zanna, A.: Lie group methods. Acta Numerica 9, 215–365 (2000)Iserles, A., Nørsett, S.P.: On the solution of linear differential equations in Lie groups. Phil. Trans. R. Soc. Lond. A 357, 983–1019 (1999)Jódar, L., Ponsoda, E.: Non-autonomous Riccati-type matrix differential equations: existence interval, construction of continuous numerical solutions and error bounds. IMA. J. Num. Anal. 15, 61–74 (1995)Jódar, L., Ponsoda, E., Company, R.: Solutions of coupled Riccati equations arising in differential games. Control. Cybern. 24, 117–128 (1995)Kaitala, V, Pohjola, M. In: Carraro, Filar (eds.) : Sustainable international agreement on greenhouse warming. A game theory study. Control and Game Theoretic Models of the Environment, pp 67–87. Birkhauser, Boston (1995)Keller, H.B.: Numerical solution of two point boundary value problems. In: CBMS-NSF Regional Conference Series in Applied Mathematics, Vol. 24. SIAM, Philadelphia (1976)McLachlan, R.I.: Composition methods in the presence of small parameters. BIT 35, 258–268 (1995)McLachlan, R.I., Quispel, R.: Splitting Methods. Acta Numer. 11, 341–434 (2002)Moler, C.B., Van Loan, C.F.: Nineteen Dubious Ways to Compute the Exponential of a Matrix, twenty-five years later. SIAM Rev. 45, 3–49 (2003)Na, T.Y.: Computational methods in engineering boundary value problems. In: Mathematics in Science and Engineering, Vol. 145. Accademic Press, New York (1979)Palao, J.P., Kosloff, R.: Quantum computing by an optimal control algorithm for unitry transformations. Phys. Rev. Lett. 28 (2002)Peirce, A.P., Dahleh, M.A., Rabitz, H.: Optimal control of quantum-mechanical systems: existence, numerical approximation, and applications. Phys. Rev. A 37, 4950–4967 (1988)Reid, W.T.: Riccati Differential Equations. Academic, New York (1972)Sanz-Serna, J.M., Calvo, M.P.: Numerical Hamiltonian Problems. Chapman & Hall, London (1994)Sidje, R.B.: Expokit: a software package for computing matrix exponentials. ACM Trans. Math. Software 24, 130–156 (1998)Speyer, J.L., Jacobson, D.H.: Primer on optimal control theory. SIAM, Philadelphia (2010)Starr, A.W., Ho, Y.C.: Non-zero sum differential games. J. Optim. Theory and Appl 3, 179–197 (1969)Zhu, W., Rabitz, H.: A rapid monotonically convergent iteration algorithm for quantum optimal control ever the expectation value of a positive definite operator. J. Chem. Phys. 109, 385–391 (1998

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Quantitative trait loci for sensitivity to ethanol intoxication in a C57BL/6J × 129S1/SvImJ inbred mouse cross

Individual variation in sensitivity to acute ethanol (EtOH) challenge is associated with alcohol drinking and is a predictor of alcohol abuse. Previous studies have shown that the C57BL/6J (B6) and 129S1/SvImJ (S1) inbred mouse strains differ in responses on certain measures of acute EtOH intoxication. To gain insight into genetic factors contributing to these differences, we performed quantitative trait locus (QTL) analysis of measures of EtOH-induced ataxia (accelerating rotarod), hypothermia, and loss of righting reflex (LORR) duration in a B6 × S1 F2 population. We confirmed that S1 showed greater EtOH-induced hypothermia (specifically at a high dose) and longer LORR compared to B6. QTL analysis revealed several additive and interacting loci for various phenotypes, as well as examples of genotype interactions with sex. QTLs for different EtOH phenotypes were largely non-overlapping, suggesting separable genetic influences on these behaviors. The most compelling main-effect QTLs were for hypothermia on chromosome 16 and for LORR on chromosomes 4 and 6. Several QTLs overlapped with loci repeatedly linked to EtOH drinking in previous mouse studies. The architecture of the traits we examined was complex but clearly amenable to dissection in future studies. Using integrative genomics strategies, plausible functional and positional candidates may be found. Uncovering candidate genes associated with variation in these phenotypes in this population could ultimately shed light on genetic factors underlying sensitivity to EtOH intoxication and risk for alcoholism in humans

Resilient emotionality and molecular compensation in mice lacking the oligodendrocyte-specific gene Cnp1

Altered oligodendrocyte structure and function is implicated in major psychiatric illnesses, including low cell number and reduced oligodendrocyte-specific gene expression in major depressive disorder (MDD). These features are also observed in the unpredictable chronic mild stress (UCMS) rodent model of the illness, suggesting that they are consequential to environmental precipitants; however, whether oligodendrocyte changes contribute causally to low emotionality is unknown. Focusing on 2′-3′-cyclic nucleotide 3′-phosphodiesterase (Cnp1), a crucial component of axoglial communication dysregulated in the amygdala of MDD subjects and UCMS-exposed mice, we show that altered oligodendrocyte integrity can have an unexpected functional role in affect regulation. Mice lacking Cnp1 (knockout, KO) displayed decreased anxiety- and depressive-like symptoms (i.e., low emotionality) compared with wild-type animals, a phenotypic difference that increased with age (3–9 months). This phenotype was accompanied by increased motor activity, but was evident before neurodegenerative-associated motor coordination deficits (⩽9–12 months). Notably, Cnp1KO mice were less vulnerable to developing a depressive-like syndrome after either UCMS or chronic corticosterone exposure. Cnp1KO mice also displayed reduced fear expression during extinction, despite normal amygdala c-Fos induction after acute stress, together implicating dysfunction of an amygdala-related neural network, and consistent with proposed mechanisms for stress resiliency. However, the Cnp1KO behavioral phenotype was also accompanied by massive upregulation of oligodendrocyte- and immune-related genes in the basolateral amygdala, suggesting an attempt at functional compensation. Together, we demonstrate that the lack of oligodendrocyte-specific Cnp1 leads to resilient emotionality. However, combined with substantial molecular changes and late-onset neurodegeneration, these results suggest the low Cnp1 seen in MDD may cause unsustainable and maladaptive molecular compensations contributing to the disease pathophysiology

Early maternal mirroring predicts infant motor system activation during facial expression observation.

Processing facial expressions is an essential component of social interaction, especially for preverbal infants. In human adults and monkeys, this process involves the motor system, with a neural matching mechanism believed to couple self- and other-generated facial gestures. Here, we used electroencephalography to demonstrate recruitment of the human motor system during observation and execution of facial expressions in nine-month-old infants, implicating this system in facial expression processing from a very young age. Notably, examination of early video-recorded mother-infant interactions supported the common, but as yet untested, hypothesis that maternal mirroring of infant facial gestures is central to the development of a neural matching mechanism for these gestures. Specifically, the extent to which mothers mirrored infant facial expressions at two months postpartum predicted infant motor system activity during observation of the same expressions at nine months. This suggests that maternal mirroring strengthens mappings between visual and motor representations of facial gestures, which increases infant neural sensitivity to particularly relevant cues in the early social environment

Sensorimotor adaptation as a behavioural biomarker of early spinocerebellar ataxia type 6.

Early detection of the behavioural deficits of neurodegenerative diseases may help to describe the pathogenesis of such diseases and establish important biomarkers of disease progression. The aim of this study was to identify how sensorimotor adaptation of the upper limb, a cerebellar-dependent process restoring movement accuracy after introduction of a perturbation, is affected at the pre-clinical and clinical stages of spinocerebellar ataxia type 6 (SCA6), an inherited neurodegenerative disease. We demonstrate that initial adaptation to the perturbation was significantly impaired in the eighteen individuals with clinical motor symptoms but mostly preserved in the five pre-clinical individuals. Moreover, the amount of error reduction correlated with the clinical symptoms, with the most symptomatic patients adapting the least. Finally both pre-clinical and clinical individuals showed significantly reduced de-adaptation performance after the perturbation was removed in comparison to the control participants. Thus, in this large study of motor features in SCA6, we provide novel evidence for the existence of subclinical motor dysfunction at a pre-clinical stage of SCA6. Our findings show that testing sensorimotor de-adaptation could provide a potential predictor of future motor deficits in SCA6

Developing adaptive control:Age-related differences in task choices and awareness of proactive and reactive control demands

Developmental changes in executive function are often explained in terms of core cognitive processes and associated neural substrates. For example, younger children tend to engage control reactively in the moment as needed, whereas older children increasingly engage control proactively, in anticipation of needing it. Such developments may reflect increasing capacities for active maintenance dependent upon dorsolateral prefrontal cortex. However, younger children will engage proactive control when reactive control is made more difficult, suggesting that developmental changes may also reflect decisions about whether to engage control, and how. We tested awareness of temporal control demands and associated task choices in 5-year-olds and 10-year-olds and adults using a demand selection task. Participants chose between one task that enabled proactive control and another task that enabled reactive control. Adults reported awareness of these different control demands and preferentially played the proactive task option. Ten-year-olds reported awareness of control demands but selected task options at chance. Five-year-olds showed neither awareness nor task preference, but a subsample who exhibited awareness of control demands preferentially played the reactive task option, mirroring their typical control mode. Thus, developmental improvements in executive function may in part reflect better awareness of cognitive demands and adaptive behavior, which may in turn reflect changes in dorsal anterior cingulate in signaling task demands to lateral prefrontal cortex