Universal Two-Electron Correlation Operator on Excited States

Excited states of chemical systems are extremely important in understanding spectra, chemical phenomena, as well as how a particular compound behaves in reactions. Computationally, excited states are normally very expensive to calculate. The difficulty in calculating these states with wavefunction based methods can be mainly attributed to the calculation of large multi-determinant wavefunctions. One reason to use a complicated multi-determinant wavefunction is to include some of the effects of correlation energy. The quantity of correlation energy can most simply be defined as the reduction in energy caused by any two or more electrons trying to avoid each other. The most common way of avoiding these computational costs is through the use of time-dependent density functional theory (TD-DFT). TD-DFT has an exceptional ratio of accuracy to computational cost because it reduces the many-electron wavefunction to a single-electron density. A single-electron quantity, however, is an improper way to descibe an innately two-electron property like correlation energy. Within this research we seek to alleviate the large computational costs required to calculate excited states with a wavefunction-based method and reduce the costs to near Hartree-Fock theory levels. We do this by using two different inexpensive excited wavefunction methods. First we reduce our multi-determinant wavefunction to a single-determinant wavefunction. The single-determinant wavefunction used in this research comes from delta self-consistent field method that essentially creates excited Hartree-Fock states. Secondly we construct the simplest multi-configurational wavefunction using a linear combination of all singly excited states with the method known as configuration interaction singles (CIS). The reduction in wavefunction size, however, reduces nearly all correlation energy recovered by both methods. This is remedied by modeling correlation energy in a computationally inexpensive manner. A potentially accurate way to model electron correlation within the single determinant wavefunction formalism is through the expectation value of a linear two-electron operator over the Kohn-Sham single-determinant wavefunction. For practical reasons, it is desirable for such an operator to be universal, i.e. independent of the positions and types of nuclei in a molecule. We choose an operator expanded in a small number of Gaussians as a model for electron correlation. The accuracy of this method is tested by computing atomic and molecular adiabatic excited states in comparison with popular TD-DFT functionals. The correlation operator combined with SCF is found to be comparable in accuracy to TD-DFT methods for both atomic and molecular excited states. SCF is limited in its applications, however, due to its inability to guarantee orthogonal excited states which leads to unwanted spin contamination. The correlation operator combined with CIS is found to be comparable in accuracy to TD-DFT methods for atomic states but has a significant loss in accuracy for excited molecular states. This drop in accuracy is theorized to be the poor description Hartree Fock theory gives of some ground and excited state wavefunctions.. We offer some possible solutions to these problems in the form of orthogonality constraints and a potential hybrid method of SCF and CIS

Fast and accurate modelling of longitudinal and repeated measures neuroimaging data

Despite the growing importance of longitudinal data in neuroimaging, the standard analysis methods make restrictive or unrealistic assumptions (e.g., assumption of Compound Symmetry—the state of all equal variances and equal correlations—or spatially homogeneous longitudinal correlations). While some new methods have been proposed to more accurately account for such data, these methods are based on iterative algorithms that are slow and failure-prone. In this article, we propose the use of the Sandwich Estimator (SwE) method which first estimates the parameters of interest with a simple Ordinary Least Square model and second estimates variances/covariances with the “so-called” SwE which accounts for the within-subject correlation existing in longitudinal data. Here, we introduce the SwE method in its classic form, and we review and propose several adjustments to improve its behaviour, specifically in small samples. We use intensive Monte Carlo simulations to compare all considered adjustments and isolate the best combination for neuroimaging data. We also compare the SwE method to other popular methods and demonstrate its strengths and weaknesses. Finally, we analyse a highly unbalanced longitudinal dataset from the Alzheimer's Disease Neuroimaging Initiative and demonstrate the flexibility of the SwE method to fit within- and between-subject effects in a single model. Software implementing this SwE method has been made freely available at http://warwick.ac.uk/tenichols/SwE

The effect of d-cycloserine on brain processing of breathlessness over pulmonary rehabilitation: an experimental medicine study

Research questionPulmonary rehabilitation is the best treatment for chronic breathlessness in COPD but there remains an unmet need to improve efficacy. Pulmonary rehabilitation has strong parallels with exposure-based cognitive behavioural therapies (CBT), both clinically and in terms of brain activity patterns. The partial N-methyl-d-aspartate (NMDA)-receptor agonistd-cycloserine has shown promising results in enhancing efficacy of CBT, thus we hypothesised that it would similarly augment the effects of pulmonary rehabilitation in the brain. Positive findings would support further development in phase 3 clinical trials.Methods72 participants with mild-to-moderate COPD were recruited to a double-blind pre-registered (ClinicalTrials.govidentifier:NCT01985750) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250 mgd-cycloserine or placebo, administered immediately prior to the first four sessions of pulmonary rehabilitation. Primary outcome measures were differences betweend-cycloserine and placebo in brain activity in the anterior insula, posterior insula, anterior cingulate cortices, amygdala and hippocampus following completion of pulmonary rehabilitation. Secondary outcomes included the same measures at an intermediate time point and voxel-wise difference across wider brain regions. An exploratory analysis determined the interaction with breathlessness anxiety.ResultsNo difference betweend-cycloserine and placebo groups was observed across the primary or secondary outcome measures.d-cycloserine was shown instead to interact with changes in breathlessness anxiety to dampen reactivity to breathlessness cues. Questionnaire and measures of respiratory function showed no group difference. This is the first study testing brain-active drugs in pulmonary rehabilitation. Rigorous trial methodology and validated surrogate end-points maximised statistical power.ConclusionAlthough increasing evidence supports therapeutic modulation of NMDA pathways to treat symptoms, we conclude that a phase 3 clinical trial ofd-cycloserine would not be worthwhile

Thirty- and ninety-day outcomes after sublobar resection with and without brachytherapy for non–small cell lung cancer: Results from a multicenter phase III study

ObjectiveSublobar resection (SR) is commonly used for patients considered high risk for lobectomy. Nonoperative therapies are increasingly being reported for patients with similar risk because of perceived lower morbidity. We report 30- and 90-day adverse events (AEs) from American College of Surgeons Oncology Group Z4032, a multicenter phase III study for high-risk patients with stage I non–small cell lung cancer.MethodsData from 222 evaluable patients randomized to SR (n = 114) or SR with brachytherapy (n = 108) are reported. AEs were recorded using the Common Terminology Criteria for Adverse Events, Version 3.0, at 30 and 90 days after surgery. Risk factors (age, percent baseline carbon monoxide diffusion in the lung [DLCO%], percent forced expiratory volume in 1 second [FEV1%], upper lobe vs lower lobe resections, performance status, surgery approach, video-assisted thoracic surgery vs open and extent, and wedge vs segmentectomy) were analyzed using a multivariable logistic model for their impact on the incidence of grade 3 or higher (G3+) AEs. Respiratory AEs were also specifically analyzed.ResultsMedian age, FEV1%, and DLCO% were similar in the 2 treatment groups. There was no difference in the location of resection (upper vs lower lobe) or the use of segmental or wedge resections. There were no differences between the groups with respect to “respiratory” G3+ AEs (30 days: 14.9% vs 19.4%, P = .35; 0–90 days: 19.3% vs 25%, P = .31) and “any” G3+ AEs (30 days: 25.4% vs 30.6%, P = .37; 0–90 days: 29.8% vs 37%, P = .25). Further analysis combined the 2 groups. Mortality occurred in 3 patients (1.4%) by 30 days and in 6 patients (2.7%) by 90 days. Four of the 6 deaths were thought to be due to surgery. When considered as continuous variables, FEV1% was associated with “any” G3+ AE at days 0 to 30 (P = .03; odds ratio [OR] = 0.98) and days 0 to 90 (P = .05; OR = 0.98), and DLCO% was associated with “respiratory” G3+ AE at days 0 to 30 (P = .03; OR = 0.97) and days 0 to 90 (P = .05; OR = 0.98). Segmental resection was associated with a higher incidence of any G3+ AE compared with wedge resection at days 0 to 30 (40.3% vs 22.7%; OR = 2.56; P < .01) and days 0 to 90 (41.5% vs 29.7%; OR = 1.96; P = .04). The median FEV1% was 50%, and the median DLCO% was 46%. By using these median values as potential cutpoints, only a DLCO% of less than 46% was significantly associated with an increased risk of “respiratory” and “any” G3+ AE for days 0 to 30 and 0 to 90.ConclusionsIn a multicenter setting, SR with brachytherapy was not associated with increased morbidity compared with SR alone. SR/SR with brachytherapy can be performed safely in high-risk patients with non–small cell lung cancer with low 30- and 90-day mortality and acceptable morbidity. Segmental resection was associated with increased “any” G3+ AE, and DLCO% less than 46% was associated with “any” G3+ AE and “respiratory” G3+ AE at both 30 and 90 days

Novel De Novo Mutation in Sulfonylurea Receptor 1 Presenting as Hyperinsulinism in Infancy Followed by Overt Diabetes in Early Adolescence

OBJECTIVE—Congenital hyperinsulinism, usually associated with severe neonatal hypoglycemia, may progress to diabetes, typically during the 4th decade of life in nonpancreatectomized patients. We aimed to genotype the ATP-sensitive K+ channel in a 10.5-year-old girl presenting with overt diabetes following hyperinsulinism in infancy

The effect of D-cycloserine on brain processing of breathlessness over pulmonary rehabilitation - an experimental medicine study

Research Question: Pulmonary rehabilitation is the best treatment for chronic breathlessness in COPD but there remains an unmet need to improve efficacy. Pulmonary rehabilitation has strong parallels with exposure-based cognitive behavioural therapies (CBT), both clinically and in terms of brain activity patterns. The partial NMDA-receptor agonist, D-cycloserine has shown promising results in enhancing efficacy of CBT, thus we hypothesised that it would similarly augment the effects of pulmonary rehabilitation in the brain. Positive findings would support further development in phase 3 clinical trials. Methods: 72 participants with mild-to-moderate COPD were recruited to a doubleblind pre-registered (ID: NCT01985750) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250mg Dcycloserine or placebo, administered immediately prior to the first four sessions of pulmonary rehabilitation. Primary outcome measures were differences between Dcycloserine and placebo in brain activity in the anterior insula, posterior insula, anterior cingulate cortices, amygdala and hippocampus following completion of pulmonary rehabilitation. Secondary outcomes included the same measures at an intermediate time point and voxel-wise difference across wider brain regions. An exploratory analysis determined the interaction with breathlessness-anxiety. Results: No difference between D-cycloserine and placebo groups was observed across the primary or secondary outcome measures. D-cycloserine was shown instead to interact with changes in breathlessness anxiety to dampen reactivity to breathlessness cues. Questionnaire and measures of respiratory function showed no group difference. This is the first study testing brain-active drugs in pulmonary rehabilitation. Rigorous trial methodology and validated surrogate end-points maximised statistical power. Conclusion: Although increasing evidence supports therapeutic modulation of NMDA pathways to treat symptoms, we conclude that a phase 3 clinical trial of D- cycloserine would not be worthwhile

1955: Abilene Christian College Bible Lectures - Full Text

Delivered in the Auditorium of Abilene Christian College, February, 1955 ABILENE, TEXAS PRICE, $3.00 FIRM FOUNDATION PUBLISHING HOUSE Box 77 Austin 61, Texa

Sedimentation during MIS 3 at the eastern margins of the Glacial Lake Humber basin, England

The stratigraphic sequence at North Cave, on the eastern margins of the Lake Humber basin, records the deposition of a fluvioperiglacial fan (LFs 1–4), with early sedimentation (LF1) dating to Marine Isotope Stage (MIS) 3 (optically stimulated luminescence date range 41.8–38.6 ka and 14C dates 41.6–49 ka BP). Three phases of permafrost and ice wedge development during MIS 3 are evident and indicate possible fan abandonment and hence periods of reduced nival runoff. Involution structures dated to 11.1 ka with large boulders and fine‐grained sorted circles in LF4b are interpreted as periglacially cryoturbated littoral deposits with boulders derived from anchor ice, initially deposited at the margins of Lake Humber up to an altitude of 8 m OD during MIS 2. The style and age of fluvioperiglacial fan deposition at North Cave is compatible with several mid‐Devensian sites around Britain characterized by significant nival melt and run‐off from steeply incised valleys in permafrozen cuesta landscapes. This phase of fluvioperiglacial fan aggradation to near or below 0 m OD is recorded around the glacial lakes Humber and Fenland basins and indicates that no glacial lakes existed at that time

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth