Using longitudinal targeted maximum likelihood estimation in complex settings with dynamic interventions.

Longitudinal targeted maximum likelihood estimation (LTMLE) has very rarely been used to estimate dynamic treatment effects in the context of time-dependent confounding affected by prior treatment when faced with long follow-up times, multiple time-varying confounders, and complex associational relationships simultaneously. Reasons for this include the potential computational burden, technical challenges, restricted modeling options for long follow-up times, and limited practical guidance in the literature. However, LTMLE has desirable asymptotic properties, ie, it is doubly robust, and can yield valid inference when used in conjunction with machine learning. It also has the advantage of easy-to-calculate analytic standard errors in contrast to the g-formula, which requires bootstrapping. We use a topical and sophisticated question from HIV treatment research to show that LTMLE can be used successfully in complex realistic settings, and we compare results to competing estimators. Our example illustrates the following practical challenges common to many epidemiological studies: (1) long follow-up time (30 months); (2) gradually declining sample size; (3) limited support for some intervention rules of interest; (4) a high-dimensional set of potential adjustment variables, increasing both the need and the challenge of integrating appropriate machine learning methods; and (5) consideration of collider bias. Our analyses, as well as simulations, shed new light on the application of LTMLE in complex and realistic settings: We show that (1) LTMLE can yield stable and good estimates, even when confronted with small samples and limited modeling options; (2) machine learning utilized with a small set of simple learners (if more complex ones cannot be fitted) can outperform a single, complex model, which is tailored to incorporate prior clinical knowledge; and (3) performance can vary considerably depending on interventions and their support in the data, and therefore critical quality checks should accompany every LTMLE analysis. We provide guidance for the practical application of LTMLE

Predicting the unknown:Novelty processing depends on expectations

Fulfilled predictions lead to neural suppression akin to repetition suppression, but it is currently unclear if such effects generalize to broader stimulus categories in the absence of exact expectations. In particular, does expecting novelty alter the way novel stimuli are processed? In the present study, the effects of expectations on novelty processing were investigated using event-related potentials, while controlling for the effect of repetition. Sequences of five stimuli were presented in a continuous way, such that the last stimulus of a 5-stimulus sequence was followed by the first stimulus of a new 5-stimulus sequence without interruption. The 5-stimulus sequence was predictable: the first three stimuli were preceded by a cue indicating that the next stimulus was likely to be a standard stimulus, and the last two by a cue indicating that the next stimulus was likely to be novel. On some trials a cue typically predicting a standard was in fact followed by an unexpected novel stimulus. This design allowed to investigate the independent effects of (violated) expectations and repetition on novelty processing. The initial detection of expected novels was enhanced compared to unexpected novels, as indexed by a larger anterior N2. In contrast, the orienting response, as reflected by a novelty P3, was reduced for expected compared to unexpected novels. Although the novel stimuli were never repeated themselves, they could be presented after one another in the sequence. Such a category repetition affected the processing of novelty, as evidenced by an enhanced anterior N2, and a reduced novelty P3 for novels preceded by other novels. Taken together, the current study shows that novelty processing is influenced by expectations

The Molecular Structure of Cyclobutane

The cyclobutane molecule has been found by electron diffraction to have the following bond distances and bond angles: C–C, 1.568±0.02A; C–H, 1.098±0.04A; ∠HCH, 114±8°. On the average the ring is nonplanar, with dihedral angle 20° (+10°, −20°), but the equilibrium symmetry may be either D_(2d) (puckered ring) or D_(4h) (planar ring with low rigidity leading to large amplitude of out‐of‐plane bending). This point is discussed in connection with earlier spectroscopic work. The long bond distances found in four‐membered rings are contrasted against the short distances in three‐membered rings, and the strain energies, bond distances, and HCH angles of cycloalkanes are discussed in terms of modern valence concepts. It is suggested that the potential energy arising from a repulsion of the nonbonded carbon atoms may contribute significantly to the apparently anomalously high strain energy of cyclobutane. The repulsive force associated with such a potential is shown to account satisfactorily for the long C–C distances

A Structure Containing Diastereomers, (2\u3ci\u3eS\u3c/i\u3e,4\u3ci\u3eR\u3c/i\u3e)-\u3ci\u3etrans\u3c/i\u3e- and (2\u3ci\u3eR\u3c/i\u3e,4\u3ci\u3eR\u3c/i\u3e)-\u3ci\u3ecis\u3c/i\u3e-2-hydroxy-2,4-dimethyl-3,4-dihydro-2\u3ci\u3eH\u3c/i\u3e,5\u3ci\u3eH\u3c/i\u3e-pyrano[3,2-\u3ci\u3ec\u3c/i\u3e][1]benzopyran-5-one, C\u3csub\u3e14\u3c/sub\u3eH\u3csub\u3e14\u3c/sub\u3eO\u3csub\u3e4\u3c/sub\u3e

Mr = 246·3, monoclinic, P21, a = 7·804 (3), b = 18·248 (8), c = 8·752 (5) Å, β = 99·59°, V = 1233 Å3, Z = 4 (2 molecules/asymmetric unit), Dx = 1·33 g cm-3, λ(Mo Kα) = 0·71067 Å, μ = 0·91 cm,-1, F(000) = 520, T = 293 K. Final R = 0·066 for 1123 observed independent intensities. The structure consists of diastereomers approximately inversionrelated through a pseudocenter of symmetry at x = 0·241 (4), z = 0·281 (3) except the 4-methyl groups. The dihydropyran rings are half chairs distorted towards the eƒ-diplanar conformation. Like molecules are hydrogen-bonded between hydroxyl and carbonyl groups along a, O···O distances being 2·781 (7) (trans) and 2· 780 (7) Å (cis)

It is all me: the effect of viewpoint on visual-vestibular recalibration

Participants performed a visual–vestibular motor recalibration task in virtual reality. The task consisted of keeping the extended arm and hand stable in space during a whole-body rotation induced by a robotic wheelchair. Performance was first quantified in a pre-test in which no visual feedback was available during the rotation. During the subsequent adaptation phase, optical flow resulting from body rotation was provided. This visual feedback was manipulated to create the illusion of a smaller rotational movement than actually occurred, hereby altering the visual–vestibular mapping. The effects of the adaptation phase on hand stabilization performance were measured during a post-test that was identical to the pre-test. Three different groups of subjects were exposed to different perspectives on the visual scene, i.e., first-person, top view, or mirror view. Sensorimotor adaptation occurred for all three viewpoint conditions, performance in the post-test session showing a marked under-compensation relative to the pre-test performance. In other words, all viewpoints gave rise to a remapping between vestibular input and the motor output required to stabilize the arm. Furthermore, the first-person and mirror view adaptation induced a significant decrease in variability of the stabilization performance. Such variability reduction was not observed for the top view adaptation. These results suggest that even if all three viewpoints can evoke substantial adaptation aftereffects, the more naturalistic first-person view and the richer mirror view should be preferred when reducing motor variability constitutes an important issue

Theory of the Thermal Diffusion of Electrolytes in a Clusius Column

A theory is presented which accounts approximately for the apparently anomalous difference between the thermal diffusion coefficients of an ion in the presence and in the absence of other electrolytes; the theory is based on the existence of an electric field parallel to the thermal gradient in the electrolyte as a consequence of the variation in mobility among the various ions present. It is pointed out also that some data on the behavior of electrolytes in a Clusius column are at variance with the Debye exponential law concerning the steady‐state distribution of solute

The Molecular Structure of Cyclopropene, C_3C_4

Cyclopropene, C_3H_4, has been investigated by the electron diffraction method. The cyclic structure is confirmed and the following interatomic distances and angles are found: C–C, 1.525±0.02 A; C=C, 1.286±0.04 A; 〈C–H〉, 1.087±0.04 A; ∠H–C–H, 118° (assumed); ∠C=C–H, 152±12°

Structures of Five \u3cem\u3etrans\u3c/em\u3e-2-Hydroxy and \u3cem\u3etrans\u3c/em\u3e-2-Methoxy-2-methyl-3,4-dihydro-4-aryl- 2\u3cem\u3eH\u3c/em\u3e,5\u3cem\u3eH\u3c/em\u3e-pyrano[3,2-\u3cem\u3ec\u3c/em\u3e]benzopyran-5-ones

Derivatives of 2-methyl-3,4-dihydro-2H,5H-pyrano[3,2-c][1]benzopyran-5-one. (1) Racemic trans-methoxy-4-phenyl, Mr = 322·4, monoclinic, P21/n, a = 5·858 (1), b = 16· 732 (9), c = 16·383 (9) Å, β = 94·82 (3)°, V = 1600·1 Å3, Z = 4, Dx = 1·338 g cm-3, λ(Mo Kα) = 0·71073 Å, μ = 0·866 cm-1, F(000) = 680, T = 298 K, final R = 0·047 for 1513 intensities. The trans methyl ketal of warfarin (C20H18O4) contains a half-chair dihydropyran ring distorted toward the d,e-diplanar conformation. (2) Resolved (2R,4R)-trans-2-methoxy-4-phenyl, Mr = 322·4, orthorhombic, P212121, a = 11·521(1), b = 14·061 (2), c = 10·055(2) Å, V = 1628·9 Å3 , Z = 4, Dx= 1·314 g cm-3, λ(Mo Kα) = 0·71073 Å, μ = 0·851 cm-1, F(000) = 680, T = 298 K, final R = 0·056 for 1660 intensities. The trans methyl ketal (C20H18O4) from R(+)-warfarin; its dihydropyran ring is a half- chair distorted toward the d,e-diplanar conformation. (3) Resolved trans-2-hydroxy-4-(4-methoxyphenyl), Mr = 338·4, orthorhombic, P212121, a = 10·584 (1), b = 10·621(5), c = 14·778 (2) Å, V = 1661·2 Å3, Z = 4, Dx = 1·353 g cm-3, λ(Mo Kα) = 0·71073 Å, μ = 0·908 cm-1, F(000) = 712, T = 298 K, final R = 0·044 for 1165 unique intensities. Compound C20H18O5 spontaneously resolves on crystallization from acetone and water, and absolute configuration of data specimen was not determined. It has a dihydropyran ring with a half-chair conformation; hydroxyl and lactone carbonyl are intermolecularly H-bonded at O···O = 2·79 Å. (4) Racemic trans-2-hydroxy-4-(2-methyl-6-methoxyphenyl), Mr = 372·4, monoclinic, P21/n, a = 9·637 (2), b = 14·345 (4), c = 13·224 (2) Å, β = 91·09 (1)°, V = 1827·8 Å3, Z = 4, Dx = 1·353 g cm-3, λ(Mo Kα) = 0·71073 Å, μ = 0·961 cm-1, F(000) = 784, T = 298 K, final R= 0·048 for 2339 unique intensities. A synthetic derivative of warfarin, it crystallizes as the hydrate C20H18O6.H2O and has a dihydropyran ring with a half-chair conformation and intermolecular H bonds with O···O distances between 2·67 and 2·77 Å. (5) Racemic trans-2-hydroxy-4-(4-dimethylaminophenyl), Mr = 369·4, triclinic, PĪ, a = 9·066 (3), b = 9·509 (2)°, c = 12·681 (3) Å, α = 98·50 (2), β = 91·25 (3), γ = 116·96 (2)°, V = 958·8 Å3, Z = 2, Dx = 1·279 g cm-3, λ(Mo Kα) = 0·71073 Å, μ = 0·854 cm-1, F(000) = 392, T = 298 K, final R = 0·045 on 2773 unique intensities. A synthetic derivative of warfarin, it also crystallizes as a hydrate, C21H21NO4.H2O, and has a dihydropyran ring with a half-chair conformation and intermolecular H bonds with O···O distances between 2·70 and 3·07 Å