Direct Determination of Optimal Real-Space Orbitals for Correlated Electronic Structure of Molecules.

We demonstrate how to determine numerically nearly exact orthonormal orbitals that are optimal for the evaluation of the energy of arbitrary (correlated) states of atoms and molecules by minimization of the energy Lagrangian. Orbitals are expressed in real space using a multiresolution spectral element basis that is refined adaptively to achieve the user-specified target precision while avoiding the ill-conditioning issues that plague AO basis set expansions traditionally used for correlated models of molecular electronic structure. For light atoms, the orbital solver, in conjunction with a variational electronic structure model [selected Configuration Interaction (CI)] provides energies of comparable precision to a state-of-the-art atomic CI solver. The computed electronic energies of atoms and molecules are significantly more accurate than the counterparts obtained with the orbital sets of the same rank expanded in Gaussian AO bases, and can be determined even when linear dependence issues preclude the use of the AO bases. It is feasible to optimize more than 100 fully correlated numerical orbitals on a single computer node, and significant room exists for additional improvement. These findings suggest that real-space orbital representations might be the preferred alternative to AO representations for high-end models of correlated electronic states of molecules and materials.

Skull metastases and osseous venous malformations: The role of diffusion-weighted and dynamic contrast-enhanced MRI.

BACKGROUND AND PURPOSE: Skull metastasis (SM) is a common secondary malignancy. We evaluated the diagnostic performance of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced magnetic resonance imaging (MRI) in differentiating SM from osseous venous malformations and SM of various origins. METHODS: This study included 31 patients with SM (median age, 64 years; range, 41-87 years; 29 women; 24 and 7 patients with breast and non-small cell lung cancer, respectively) and 16 with osseous venous malformations (median age, 68 years; range, 20-81 years; 10 women) who underwent both DWI and dynamic contrast-enhanced MRI between January 2015 and October 2021. Normalized mean apparent diffusion coefficients (ADCs) and dynamic contrast-enhanced MRI parameters were compared between SM and osseous venous malformations, and between breast cancer and non-small cell lung cancer. Multivariate stepwise logistic regression analyses were performed to identify statistically significant parameters. RESULTS: Plasma volume and time-to-maximum enhancement were the most statistically significant parameters for differentiating SM from osseous venous malformations, with an area under the receiver operating characteristic curve of 0.962. The normalized mean ADC and peak enhancement values were the most statistically significant parameters for differentiating breast cancer from non-small cell lung cancer, with an area under the curve of 0.924. CONCLUSIONS: Our results highlight the efficacious diagnostic performance of DWI and dynamic contrast-enhanced MRI in distinguishing SM from osseous venous malformations and differentiating SM of various origins.

Dynamic susceptibility contrast and diffusion-weighted MRI in posterior fossa pilocytic astrocytoma and medulloblastoma.

BACKGROUND AND PURPOSE: The utility of perfusion MRI in distinguishing between pilocytic astrocytoma (PA) and medulloblastoma (MB) is unclear. This study aimed to evaluate the diagnostic and prognostic performance of dynamic susceptibility contrast (DSC)-MRI parameters and apparent diffusion coefficient (ADC) values between PA and MB. METHODS: Between January 2012 and August 2021, 49 (median, 7 years [range, 1-28 years]; 28 females) and 35 (median, 8 years [1-24 years]; 12 females) patients with pathologically confirmed PA and MB, respectively, were included. The normalized relative cerebral blood volume and flow (nrCBV and nrCBF) and mean and minimal normalized ADC (nADCmean and nADCmin) values were calculated using volume-of-interest analyses. Diagnostic performance and Pearson's correlation with progression-free survival were also evaluated. RESULTS: The MB group showed a significantly higher nrCBV and nrCBF (nrCBV: 1.69 [0.93-4.23] vs. 0.95 [range, 0.37-2.28], p = .0032; nrCBF: 1.62 [0.93-3.16] vs. 1.07 [0.46-2.26], p = .0084) and significantly lower nADCmean and nADCmin (nADCmean: 0.97 [0.70-1.68] vs. 2.21 [1.44-2.80], p < .001; nADCmin: 0.50 [0.19-0.89] vs. 1.42 [0.89-2.20], p < .001) than the PA group. All parameters exhibited good diagnostic ability (accuracy >0.80) with nADCmin achieving the highest score (accuracy = 1). A moderate correlation was found between nADCmean and progression-free survival for MB (r = 0.44, p = .0084). CONCLUSIONS: DSC-MRI parameters and ADC values were useful for distinguishing between PA and MB. A lower ADC indicated an unfavorable MB prognosis, but the DSC-MRI parameters did not correlate with progression-free survival in either group.

Management of the positive sentinel lymph node in the post-MSLT-II era.

BACKGROUND AND OBJECTIVES: The publication of MSLT-II shifted recommendations for management of sentinel lymph node biopsy positive (SLNB+) melanoma to favor active surveillance. We examined trends in immediate completion lymph node dissection (CLND) following publication of MSLT-II. METHODS: Using a prospective melanoma database at a high-volume center, we identified a cohort of consecutive SLNB+ patients from July 2016 to April 2019. Patient and disease characteristics were analyzed with multivariate logistic regression to examine factors associated with CLND. RESULTS: Two hundred and thirty-five patients were included for analysis. CLND rates were 67%, 33%, and 26% for the year before, year after, and second-year following MSLT-II. Factors associated with undergoing CLND included primary located in the head and neck (59% vs 33%, P = .003 and odds ratio [OR], 5.22, P = .002) and higher sentinel node tumor burden (43% vs 10% for tumor burden ≥0.1 mm, P < .001 and OR, 8.64, P = .002). CONCLUSIONS: Rates of CLND in SLNB+ melanoma decreased dramatically, albeit not uniformly, following MSLT-II. Factors that increased the likelihood of immediate CLND were primary tumor located in the head and neck and high sentinel node tumor burden. These groups were underrepresented in MSLT-II, suggesting that clinicians are wary of implementing active surveillance recommendations for patients perceived as higher risk.

In situ metabolite and lipid analysis of GluN2D-/- and wild-type mice after ischemic stroke using MALDI MSI.

The N-methyl-D-aspartate (NMDA) receptor is a crucial mediator of pathological glutamate-driven excitotoxicity and subsequent neuronal death in acute ischemic stroke. Although the roles of the NMDAR's composite GluN2A-C subunits have been investigated in this phenomenon, the relative importance of the GluN2D subunit has yet to be evaluated. Herein, GluN2D-/- mice were studied in a model of ischemic stroke using MALDI FT-ICR mass spectrometry imaging to investigate the role of the GluN2D subunit of the NMDA receptor in brain ischemia. GluN2D-/- mice underwent middle cerebral artery occlusion (MCAO) and brain tissue was subsequently harvested, frozen, and cryosectioned. Tissue sections were analyzed via MALDI FT-ICR mass spectrometry imaging. MALDI analyses revealed increases in several calcium-related species, namely vitamin D metabolites, LysoPC, and several PS species, in wild-type mouse brain tissue when compared to wild type. In addition, GluN2D-/- mice also displayed an increase in PC, as well as a decrease in DG, suggesting reduced free fatty acid release from brain ischemia. These trends indicate that GluN2D-/- mice show enhanced rates of neurorecovery and neuroprotection from ischemic strokes compared to wild-type mice. The cause of neuroprotection may be the result of an increase in PGP in knockout mice, contributing to greater cardiolipin synthesis and decreased sensitivity to apoptotic signals. Graphical abstract.

Stable genetic integration of a red fluorescent protein in a virulent Group A Streptococcus strain.

There are several advantages, both in vitro and in vivo, in utilizing bacteria that express a fluorescent protein. Such a protein can be transiently incorporated into the bacteria or integrated within the bacterial genome. The most widely utilized fluorescent protein is green fluorescent protein (GFP), but limitations exist on its use. Additional fluorescent proteins have been designed that have many advantages over GFP and technologies for their incorporation into bacteria have been optimized. In the current study, we report the successful integration and expression of a stable fluorescent reporter, mCherry (red fluorescent protein, RFP), into the genome of a human pathogen, Group A Streptococcus pyogenes (GAS) isolate AP53(S-). RFP was targeted at the atg codon of the fcR pseudogene that is present in the mga regulon of AP53(S-). Transcription of critical bacterial genes was not functionally altered by the genomic integration of mCherry. Host virulence both in vitro (keratinocyte infection and cytotoxicity) and in vivo (skin infection) was maintained in AP53(S-)-RFP. Additionally, survival of mice infected with either AP53(S-) or AP53(S-)-RFP was similar, demonstrating that overall pathogenicity of the AP53(S-) strain was not altered by the expression of mCherry. These studies demonstrate the feasibility of integrating a fluorescent reporter into the bacterial genome of a naturally virulent isolate of Group A S. pyogenes for comparative experimental studies.

Fast semistochastic heat-bath configuration interaction.

This paper presents in detail our fast semistochastic heat-bath configuration interaction (SHCI) method for solving the many-body Schrödinger equation. We identify and eliminate computational bottlenecks in both the variational and perturbative steps of the SHCI algorithm. We also describe the parallelization and the key data structures in our implementation, such as the distributed hash table. The improved SHCI algorithm enables us to include in our variational wavefunction two orders of magnitude more determinants than has been reported previously with other selected configuration interaction methods. We use our algorithm to calculate an accurate benchmark energy for the chromium dimer with the X2C relativistic Hamiltonian in the cc-pVDZ-DK basis, correlating 28 electrons in 76 spatial orbitals. Our largest calculation uses two billion Slater determinants in the variational space and semistochastically includes perturbative contributions from at least trillions of additional determinants with better than 10-5 Ha statistical uncertainty.

Excited States of Methylene, Polyenes, and Ozone from Heat-Bath Configuration Interaction.

The electronically excited states of methylene (CH2), ethylene (C2H4), butadiene (C4H6), hexatriene (C6H8), and ozone (O3) have long proven challenging due to their complex mixtures of static and dynamic correlations. The semistochastic heat-bath configuration interaction (SHCI) algorithm, which efficiently and systematically approaches the full configuration interaction (FCI) limit, is used to provide close approximations to the FCI energies in these systems. This article presents the largest FCI-level calculation to date on hexatriene, using a polarized double-ζ basis (ANO-L-pVDZ), which gives rise to a Hilbert space containing more than 1038 determinants. These calculations give vertical excitation energies of 5.58 and 5.59 eV, respectively, for the 21Ag and 11Bu states, showing that they are nearly degenerate. The same excitation energies in butadiene/ANO-L-pVDZ were found to be 6.58 and 6.45 eV. In addition to these benchmarks, our calculations strongly support the presence of a previously hypothesized ring-minimum species of ozone that lies 1.3 eV higher than the open-ring-minimum energy structure and is separated from it by a barrier of 1.11 eV.

A deficiency of the GluN2C subunit of the N-methyl-D-aspartate receptor is neuroprotective in a mouse model of ischemic stroke.

The N-methyl-D-aspartate receptor (NMDAR) ion channel plays a pivotal role in the pathology of ischemic stroke. The functional receptor consists of two GluN1 subunits (a-h) and two GluN2 subunits (A/B/C/D), the expression of which are spatially and temporally regulated in pathological and physiological conditions. While the roles of the GluN2A and GluN2B subunit in ischemic stroke have been well developed, the role of the GluN2C subunit in ischemia is not well understood. Following middle carotid artery occlusion (MCAO), GluN2C-/- male mice displayed similar volumes of infarct as wild-type (WT) mice. However, GluN2C-/- mice showed decreased cerebral edema and an enhanced rate of neurological recovery compared to WT mice. The ischemic penumbra of GluN2C-/- mice showed fewer cytoarchitectural deficits and decreased tauopathy relative to WT mice. These neuroprotective changes in GluN2C-/- mice also corresponded with decreased expression of Fyn kinase and decreased phosphorylation of GluN2B subunit at Tyr1336. Lastly, a GluN2C deficiency modified the NMDAR/pro-survival signaling axis, as shown by increased levels of nuclear CREB(P-Ser133). Thus, the GluN2C subunit enhances ischemic stroke pathology by promoting neuronal dysfunction in the penumbra region.

Excited states using semistochastic heat-bath configuration interaction.

We extend our recently developed heat-bath configuration interaction (HCI) algorithm, and our semistochastic algorithm for performing multireference perturbation theory, to calculate excited-state wavefunctions and energies. We employ time-reversal symmetry, which reduces the memory requirements by more than a factor of two. An extrapolation technique is introduced to reliably extrapolate HCI energies to the full CI limit. The resulting algorithm is used to compute fourteen low-lying potential energy surfaces of the carbon dimer using the cc-pV5Z basis set, with an estimated error in energy of 30-50 µHa compared to full CI. The excitation energies obtained using our algorithm have a mean absolute deviation of 0.02 eV compared to experimental values.

Cheap and Near Exact CASSCF with Large Active Spaces.

We use the recently developed Heat-bath Configuration Interaction (HCI) algorithm as an efficient active space solver to perform multiconfiguration self-consistent field calculations (HCISCF) with large active spaces. We give a detailed derivation of the theory and show that difficulties associated with non-variationality of the HCI procedure can be overcome by making use of the Lagrangian formulation to calculate the HCI relaxed two-body reduced density matrix. HCISCF is then used to study the electronic structure of butadiene, pentacene, and Fe-porphyrin. One of the most striking results of our work is that the converged active space orbitals obtained from HCISCF are relatively insensitive to the accuracy of the HCI calculation. This allows us to obtain nearly converged CASSCF energies with an estimated error of less than 1 mHa using the orbitals obtained from the HCISCF procedure in which the integral transformation is the dominant cost. For example, an HCISCF calculation on the Fe-porphyrin model complex with an active space of (44e, 44o) took only 412 s per iteration on a single node containing 28 cores, out of which 185 s was spent in the HCI calculation and the remaining 227 s was used mainly for integral transformation. Finally, we also show that active space orbitals can be optimized using HCISCF to substantially speed up the convergence of the HCI energy to the Full CI limit because HCI is not invariant to unitary transformations within the active space.

Semistochastic Heat-Bath Configuration Interaction Method: Selected Configuration Interaction with Semistochastic Perturbation Theory.

We extend the recently proposed heat-bath configuration interaction (HCI) method [Holmes, Tubman, Umrigar, J. Chem. Theory Comput. 2016, 12, 3674], by introducing a semistochastic algorithm for performing multireference Epstein-Nesbet perturbation theory, in order to completely eliminate the severe memory bottleneck of the original method. The proposed algorithm has several attractive features. First, there is no sign problem that plagues several quantum Monte Carlo methods. Second, instead of using Metropolis-Hastings sampling, we use the Alias method to directly sample determinants from the reference wave function, thus avoiding correlations between consecutive samples. Third, in addition to removing the memory bottleneck, semistochastic HCI (SHCI) is faster than the deterministic variant for many systems if a stochastic error of 0.1 mHa is acceptable. Fourth, within the SHCI algorithm one can trade memory for a modest increase in computer time. Fifth, the perturbative calculation is embarrassingly parallel. The SHCI algorithm extends the range of applicability of the original algorithm, allowing us to calculate the correlation energy of very large active spaces. We demonstrate this by performing calculations on several first row dimers including F2 with an active space of (14e, 108o), Mn-Salen cluster with an active space of (28e, 22o), and Cr2 dimer with up to a quadruple-ζ basis set with an active space of (12e, 190o). For these systems we were able to obtain better than 1 mHa accuracy with a wall time of merely 55 s, 37 s, and 56 min on 1, 1, and 4 nodes, respectively.

Heat-Bath Configuration Interaction: An Efficient Selected Configuration Interaction Algorithm Inspired by Heat-Bath Sampling.

We introduce a new selected configuration interaction plus perturbation theory algorithm that is based on a deterministic analog of our recent efficient heat-bath sampling algorithm. This Heat-bath Configuration Interaction (HCI) algorithm makes use of two parameters that control the trade-off between speed and accuracy, one which controls the selection of determinants to add to a variational wave function and one which controls the selection of determinants used to compute the perturbative correction to the variational energy. We show that HCI provides an accurate treatment of both static and dynamic correlation by computing the potential energy curve of the multireference carbon dimer in the cc-pVDZ basis. We then demonstrate the speed and accuracy of HCI by recovering the full configuration interaction energy of both the carbon dimer in the cc-pVTZ basis and the strongly correlated chromium dimer in the Ahlrichs VDZ basis, correlating all electrons, to an accuracy of better than 1 mHa, in just a few minutes on a single core. These systems have full variational spaces of 3 × 10(14) and 2 × 10(22) determinants, respectively.

Efficient Heat-Bath Sampling in Fock Space.

We introduce an algorithm for sampling many-body quantum states in Fock space. The algorithm efficiently samples states with probability approximately proportional to an arbitrary function of the second-quantized Hamiltonian matrix element connecting the sampled state to the current state. We apply the new sampling algorithm to the recently developed semistochastic full configuration interaction quantum Monte Carlo (S-FCIQMC) method, a semistochastic implementation of the power method for projecting out the ground state energy in a basis of Slater determinants. Our new sampling method requires modest additional computational time and memory compared to uniform sampling but results in newly spawned weights that are approximately of the same magnitude, thereby greatly improving the efficiency of projection. A comparison in efficiency between our sampling algorithm and uniform sampling is performed on the all-electron nitrogen dimer at equilibrium in Dunning's cc-pVXZ basis sets with X ∈ {D, T, Q, 5}, demonstrating a large gain in efficiency that increases with basis set size. In addition, a comparison in efficiency is performed on three all-electron first-row dimers, B2, N2, and F2, in a cc-pVQZ basis, demonstrating that the gain in efficiency compared to uniform sampling also increases dramatically with the number of electrons.

Fatal cardiac arrhythmia in a patient with thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP), a well-recognized syndrome with typical diagnostic features, has been implicated in rare causes of sudden death. Involvement of TTP on the myocardium and cardiac conduction system has been characterized, but the consequences related to these effects are infrequently reported. The outcome is almost always death, thus underscoring the need for early detection and therapy. A case is reported of a 36-year-old man who suffered a fatal cardiac arrhythmia related to intramyocardial hemorrhage with a diagnosis of TTP established by postmortem examination.