6 results
Characterisation of age and polarity at onset in bipolar disorder
- Janos L. Kalman, Loes M. Olde Loohuis, Annabel Vreeker, Andrew McQuillin, Eli A. Stahl, Douglas Ruderfer, Maria Grigoroiu-Serbanescu, Georgia Panagiotaropoulou, Stephan Ripke, Tim B. Bigdeli, Frederike Stein, Tina Meller, Susanne Meinert, Helena Pelin, Fabian Streit, Sergi Papiol, Mark J. Adams, Rolf Adolfsson, Kristina Adorjan, Ingrid Agartz, Sofie R. Aminoff, Heike Anderson-Schmidt, Ole A. Andreassen, Raffaella Ardau, Jean-Michel Aubry, Ceylan Balaban, Nicholas Bass, Bernhard T. Baune, Frank Bellivier, Antoni Benabarre, Susanne Bengesser, Wade H Berrettini, Marco P. Boks, Evelyn J. Bromet, Katharina Brosch, Monika Budde, William Byerley, Pablo Cervantes, Catina Chillotti, Sven Cichon, Scott R. Clark, Ashley L. Comes, Aiden Corvin, William Coryell, Nick Craddock, David W. Craig, Paul E. Croarkin, Cristiana Cruceanu, Piotr M. Czerski, Nina Dalkner, Udo Dannlowski, Franziska Degenhardt, Maria Del Zompo, J. Raymond DePaulo, Srdjan Djurovic, Howard J. Edenberg, Mariam Al Eissa, Torbjørn Elvsåshagen, Bruno Etain, Ayman H. Fanous, Frederike Fellendorf, Alessia Fiorentino, Andreas J. Forstner, Mark A. Frye, Janice M. Fullerton, Katrin Gade, Julie Garnham, Elliot Gershon, Michael Gill, Fernando S. Goes, Katherine Gordon-Smith, Paul Grof, Jose Guzman-Parra, Tim Hahn, Roland Hasler, Maria Heilbronner, Urs Heilbronner, Stephane Jamain, Esther Jimenez, Ian Jones, Lisa Jones, Lina Jonsson, Rene S. Kahn, John R. Kelsoe, James L. Kennedy, Tilo Kircher, George Kirov, Sarah Kittel-Schneider, Farah Klöhn-Saghatolislam, James A. Knowles, Thorsten M. Kranz, Trine Vik Lagerberg, Mikael Landen, William B. Lawson, Marion Leboyer, Qingqin S. Li, Mario Maj, Dolores Malaspina, Mirko Manchia, Fermin Mayoral, Susan L. McElroy, Melvin G. McInnis, Andrew M. McIntosh, Helena Medeiros, Ingrid Melle, Vihra Milanova, Philip B. Mitchell, Palmiero Monteleone, Alessio Maria Monteleone, Markus M. Nöthen, Tomas Novak, John I. Nurnberger, Niamh O'Brien, Kevin S. O'Connell, Claire O'Donovan, Michael C. O'Donovan, Nils Opel, Abigail Ortiz, Michael J. Owen, Erik Pålsson, Carlos Pato, Michele T. Pato, Joanna Pawlak, Julia-Katharina Pfarr, Claudia Pisanu, James B. Potash, Mark H Rapaport, Daniela Reich-Erkelenz, Andreas Reif, Eva Reininghaus, Jonathan Repple, Hélène Richard-Lepouriel, Marcella Rietschel, Kai Ringwald, Gloria Roberts, Guy Rouleau, Sabrina Schaupp, William A Scheftner, Simon Schmitt, Peter R. Schofield, K. Oliver Schubert, Eva C. Schulte, Barbara Schweizer, Fanny Senner, Giovanni Severino, Sally Sharp, Claire Slaney, Olav B. Smeland, Janet L. Sobell, Alessio Squassina, Pavla Stopkova, John Strauss, Alfonso Tortorella, Gustavo Turecki, Joanna Twarowska-Hauser, Marin Veldic, Eduard Vieta, John B. Vincent, Wei Xu, Clement C. Zai, Peter P. Zandi, Psychiatric Genomics Consortium (PGC) Bipolar Disorder Working Group, International Consortium on Lithium Genetics (ConLiGen), Colombia-US Cross Disorder Collaboration in Psychiatric Genetics, Arianna Di Florio, Jordan W. Smoller, Joanna M. Biernacka, Francis J. McMahon, Martin Alda, Bertram Müller-Myhsok, Nikolaos Koutsouleris, Peter Falkai, Nelson B. Freimer, Till F.M. Andlauer, Thomas G. Schulze, Roel A. Ophoff
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- Journal:
- The British Journal of Psychiatry / Volume 219 / Issue 6 / December 2021
- Published online by Cambridge University Press:
- 25 August 2021, pp. 659-669
- Print publication:
- December 2021
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Background
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
AimsTo examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
MethodGenome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
ResultsEarlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
ConclusionsAAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
Residual streaming flows in buoyancy-driven cross-shore exchange
- W. Coenen, A.L. Sánchez, R. Félez, K.A. Davis, G. Pawlak
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- Journal:
- Journal of Fluid Mechanics / Volume 920 / 10 August 2021
- Published online by Cambridge University Press:
- 04 June 2021, A1
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We present an analytical study of two-dimensional flow in a wedge driven by a time-dependent surface heat flux as a model problem to understand buoyancy-induced cross-shore flow. Besides the turbulent Prandtl number and the relevant Rayleigh number, both assumed to be of order unity, the solution is seen to depend on the geometry through a parameter $\beta$, representing the bottom slope. An analytic solution is sought in the asymptotic limit $\beta \ll 1$ for a water layer bounded by an adiabatic bottom surface subject to a harmonic heat flux on the upper surface. The analysis reveals that the motion at leading order can be expressed as the sum of a harmonic component and a steady component, the latter driven by nonlinear advection. This steady-streaming motion includes a near-shore vortex with associated recirculating motion that can affect cross-shore transport and dispersion in coastal environments. The analytical solution is compared with numerical solutions of the complete conservation equations for small values of $\beta$. Excellent quantitative agreement is found for values of the Rayleigh number below a critical value at which the periodic solution undergoes a period-doubling bifurcation, leading to the establishment of thermal-instability cells that dominate the offshore flow dynamics, while the near-shore dynamics remains well described by the analytical solution. The analysis illustrates that a periodic heat input that leads to a vertically inhomogeneous temperature distribution can result in residual motion, net heat fluxes and persistent temperature structure in the cross-shore direction.
On the dispersion of a drug delivered intrathecally in the spinal canal
- J. J. Lawrence, W. Coenen, A. L. Sánchez, G. Pawlak, C. Martínez-Bazán, V. Haughton, J. C. Lasheras
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- Journal:
- Journal of Fluid Mechanics / Volume 861 / 25 February 2019
- Published online by Cambridge University Press:
- 27 December 2018, pp. 679-720
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This paper investigates the transport of a solute carried by the cerebrospinal fluid (CSF) in the spinal canal. The analysis is motivated by the need for a better understanding of drug dispersion in connection with intrathecal drug delivery (ITDD), a medical procedure used for treatment of some cancers, infections and pain, involving the delivery of the drug to the central nervous system by direct injection into the CSF via the lumbar route. The description accounts for the CSF motion in the spinal canal, described in our recent publication (Sánchez et al., J. Fluid Mech., vol. 841, 2018, pp. 203–227). The Eulerian velocity field includes an oscillatory component with angular frequency $\unicode[STIX]{x1D714}$, equal to that of the cardiac cycle, and associated tidal volumes that are a factor $\unicode[STIX]{x1D700}\ll 1$ smaller than the total CSF volume in the spinal canal, with the small velocity corrections resulting from convective acceleration providing a steady-streaming component with characteristic residence times of order $\unicode[STIX]{x1D700}^{-2}\unicode[STIX]{x1D714}^{-1}\gg \unicode[STIX]{x1D714}^{-1}$. An asymptotic analysis for $\unicode[STIX]{x1D700}\ll 1$ accounting for the two time scales $\unicode[STIX]{x1D714}^{-1}$ and $\unicode[STIX]{x1D700}^{-2}\unicode[STIX]{x1D714}^{-1}$ is used to investigate the prevailing drug-dispersion mechanisms and their dependence on the solute diffusivity, measured by the Schmidt number $S$. Convective transport driven by the time-averaged Lagrangian velocity, obtained as the sum of the Eulerian steady-streaming velocity and the Stokes-drift velocity associated with the non-uniform pulsating flow, is found to be important for all values of $S$. By way of contrast, shear-enhanced Taylor dispersion, which is important for values of $S$ of order unity, is shown to be negligibly small for the large values $S\sim \unicode[STIX]{x1D700}^{-2}\gg 1$ corresponding to the molecular diffusivities of all ITDD drugs. Results for a model geometry indicate that a simplified equation derived in the intermediate limit $1\ll S\ll \unicode[STIX]{x1D700}^{-2}$ provides sufficient accuracy under most conditions, and therefore could constitute an attractive reduced model for future quantitative analyses of drug dispersion in the spinal canal. The results can be used to quantify dependences of the drug-dispersion rate on the frequency and amplitude of the pulsation of the intracranial pressure, the compliance and specific geometry of the spinal canal and the molecular diffusivity of the drug.
On the bulk motion of the cerebrospinal fluid in the spinal canal
- A. L. Sánchez, C. Martínez-Bazán, C. Gutiérrez-Montes, E. Criado-Hidalgo, G. Pawlak, W. Bradley, V. Haughton, J. C. Lasheras
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- Journal:
- Journal of Fluid Mechanics / Volume 841 / 25 April 2018
- Published online by Cambridge University Press:
- 20 February 2018, pp. 203-227
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Radionuclide scanning images published in Nature by Di Chiro in 1964 showed a downward migration along the spinal canal of particle tracers injected in the brain ventricles while also showing an upward flow of tracers injected in the lumbar region of the canal. These observations, since then corroborated by many radiological measurements, have been the basis for the hypothesis that there must be an active circulation mechanism associated with the transport of cerebrospinal fluid (CSF) deep down into the spinal canal and subsequently returning a portion back to the cranial vault. However, to date, there has been no physical explanation for the mechanism responsible for the establishment of such a bulk recirculating motion. To investigate the origin and characteristics of this recirculating flow, we have analyzed the motion of the CSF in the subarachnoid space of the spinal canal. Our analysis accounts for the slender geometry of the spinal canal, the small compliance of the dura membrane enclosing the CSF in the canal, and the fact that the CSF is confined to a thin annular subarachnoid space surrounding the spinal cord. We apply this general formulation to study the characteristics of the flow generated in a simplified model of the spinal canal consisting of a slender compliant cylindrical pipe with a coaxial cylindrical inclusion, closed at its distal end, and subjected to small periodic pressure pulsations at its open entrance. We show that the balance between the local acceleration and viscous forces produces a leading-order flow consisting of pure oscillatory motion with axial velocities on the order of a few centimetres per second and amplitudes monotonically decreasing along the length of the canal. We then demonstrate that the nonlinear term associated with the convective acceleration contributes to a second-order correction consisting of a steady streaming that generates a bulk recirculating motion of the CSF along the length of the canal with characteristic velocities two orders of magnitude smaller than the leading-order oscillatory flow. The results of the analysis of this idealized geometry of the spinal canal are shown to be in good agreement not only with experimental measurements in an in-vitro model but also with radiological measurements conducted in human adults.
Mixing and entrainment in developing stratified currents
- G. PAWLAK, L. ARMI
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- Journal:
- Journal of Fluid Mechanics / Volume 424 / 10 December 2000
- Published online by Cambridge University Press:
- 16 November 2000, pp. 45-73
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The spatially developing region of a steady downslope current in transition from a hydraulically controlled, arrested wedge flow is examined through a set of laboratory experiments. The mixing and entrainment mechanisms at the shear interface are explored with the use of imaging techniques. The initial, unstable accelerating region, characterized by rapid development, low shear layer Richardson numbers and high entrainment rates, is limited by the effects of stratification which suppress the large-scale overturning. A subsequent high Richardson number region is characterized by weak entrainment and the collapse of turbulence from the initial region. The flow approaches a quasi-stable state as the mixed layer draws energy from the accelerating density current. Observed large-scale structure is attributed to an instability of the marginally unstable shear layer. Entrainment rates are calculated within each region for the various slopes considered and estimates for the extent of the transition regions are obtained.
Vortex dynamics in a spatially accelerating shear layer
- G. PAWLAK, L. ARMI
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- Journal:
- Journal of Fluid Mechanics / Volume 376 / 10 December 1998
- Published online by Cambridge University Press:
- 10 December 1998, pp. 1-35
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An experimental and analytical study into the vortex dynamics of a stratified shear layer subjected to a spatial acceleration is presented. The outer flow is dictated by a hydraulically controlled wedge flow which provides a spatially accelerating shear layer and baroclinic generation of vorticity along the inclined interface. A new, finite-amplitude mechanism is observed in which the core of the growing vortex is separated from the vorticity source at the interface. A secondary core develops and an altered vortex pairing interaction is observed. A spatial linear stability analysis reveals that one of two modified Kelvin–Helmholtz modes is dominant, resulting in the centre of the instability being offset from the density interface into the slower moving stream. Digital particle imaging velocimetry (DPIV) measurements are presented along with flow visualization which indicate that the mechanism is a result of the offset in the vortex core from the source of vorticity at the interface combined with the effects of spatial acceleration and buoyancy. The mixing induced by the interfacial instabilities is such that a sharp density interface remains near the high-momentum stream, with a low-gradient region extending into the low-momentum stream.