In vivo disentanglement of diffusion frequency-dependence, tensor shape, and relaxation using multidimensional MRI.

Diffusion MRI with free gradient waveforms, combined with simultaneous relaxation encoding, referred to as multidimensional MRI (MD-MRI), offers microstructural specificity in complex biological tissue. This approach delivers intravoxel information about the microstructure, local chemical composition, and importantly, how these properties are coupled within heterogeneous tissue containing multiple microenvironments. Recent theoretical advances incorporated diffusion time dependency and integrated MD-MRI with concepts from oscillating gradients. This framework probes the diffusion frequency, ω $$ \omega $$ , in addition to the diffusion tensor, D $$ \mathbf{D} $$ , and relaxation, R 1 $$ {R}_1 $$ , R 2 $$ {R}_2 $$ , correlations. A D ω - R 1 - R 2 $$ \mathbf{D}\left(\omega \right)-{R}_1-{R}_2 $$ clinical imaging protocol was then introduced, with limited brain coverage and 3 mm3 voxel size, which hinder brain segmentation and future cohort studies. In this study, we introduce an efficient, sparse in vivo MD-MRI acquisition protocol providing whole brain coverage at 2 mm3 voxel size. We demonstrate its feasibility and robustness using a well-defined phantom and repeated scans of five healthy individuals. Additionally, we test different denoising strategies to address the sparse nature of this protocol, and show that efficient MD-MRI encoding design demands a nuanced denoising approach. The MD-MRI framework provides rich information that allows resolving the diffusion frequency dependence into intravoxel components based on their D ω - R 1 - R 2 $$ \mathbf{D}\left(\omega \right)-{R}_1-{R}_2 $$ distribution, enabling the creation of microstructure-specific maps in the human brain. Our results encourage the broader adoption and use of this new imaging approach for characterizing healthy and pathological tissues.

W4Λ: Leveraging Λ Coupled-Cluster for Accurate Computational Thermochemistry Approaches.

High-accuracy composite wave function methods like Weizmann-4 (W4) theory, high-accuracy extrapolated ab initio thermochemistry (HEAT), and the Feller-Peterson-Dixon (FPD) approach enable sub-kJ/mol accuracy in gas-phase thermochemical properties. Their biggest computational bottleneck is the evaluation of the valence post-CCSD(T) correction term. We demonstrate here, for the W4-17 thermochemistry benchmark and subsets thereof, that the Λ coupled-cluster expansion converges more rapidly and smoothly than the regular coupled-cluster series. By means of CCSDT(Q)Λ and CCSDTQ(5)Λ, we can considerably (up to an order of magnitude) accelerate W4- and W4.3-type calculations without loss in accuracy, leading to the W4Λ and W4.3Λ computational thermochemistry protocols.

On the sensitivity of computed partial charges toward basis set and (exchange-)correlation treatment.

Partial charges are a central concept in general chemistry and chemical biology, yet dozens of different computational definitions exist. In prior work [Cho et al., ChemPhysChem 21, 688-696 (2020)], we showed that these can be reduced to at most three 'principal components of ionicity'. The present study addressed the dependence of computed partial charges q on 1-particle basis set and (for WFT methods) n -particle correlation treatment or (for DFT methods) exchange-correlation functional, for several representative partial charge definitions such as QTAIM, Hirshfeld, Hirshfeld-I, HLY (electrostatic), NPA, and GAPT. Our findings show that semi-empirical double hybrids can closely approach the CCSD(T) 'gold standard' for this property. In fact, owing to an error compensation in MP2, CCSD partial charges are further away from CCSD(T) than is MP2. The nonlocal correlation is important, especially when there is a substantial amount of nonlocal exchange. Employing range separation proves to be "mostly" not advantageous, while global hybrids perform optimally for 20%-30% Hartree-Fock exchange across all charge types. Basis set convergence analysis shows that an augmented triple-zeta heavy-aug-cc-pV(T+d)Z basis set or a partially augmented jun-cc-pV(T+d)Z basis set is sufficient for Hirshfeld, Hirshfeld-I, HLY, and GAPT charges. In contrast, QTAIM and NPA display slower basis set convergence. It is noteworthy that for both NPA and QTAIM, HF exhibits markedly slower basis set convergence than the correlation components of MP2 and CCSD. Triples corrections in CCSD(T), denoted as CCSD(T)-CCSD, exhibit even faster basis set convergence.

In vivo disentanglement of diffusion frequency-dependence, tensor shape, and relaxation using multidimensional MRI.

Diffusion MRI with free gradient waveforms, combined with simultaneous relaxation encoding, referred to as multidimensional MRI (MD-MRI), offers microstructural specificity in complex biological tissue. This approach delivers intravoxel information about the microstructure, local chemical composition, and importantly, how these properties are coupled within heterogeneous tissue containing multiple microenvironments. Recent theoretical advances incorporated diffusion time dependency and integrated MD-MRI with concepts from oscillating gradients. This framework probes the diffusion frequency, ω, in addition to the diffusion tensor, D, and relaxation, R1, R2, correlations. A D(ω)-R1-R2 clinical imaging protocol was then introduced, with limited brain coverage and 3 mm3 voxel size, which hinder brain segmentation and future cohort studies. In this study, we introduce an efficient, sparse in vivo MD-MRI acquisition protocol providing whole brain coverage at 2 mm3 voxel size. We demonstrate its feasibility and robustness using a well-defined phantom and repeated scans of five healthy individuals. Additionally, we test different denoising strategies to address the sparse nature of this protocol, and show that efficient MD-MRI encoding design demands a nuanced denoising approach. The MD-MRI framework provides rich information that allows resolving the diffusion frequency dependence into intravoxel components based on their D(ω)-R1-R2 distribution, enabling the creation of microstructure-specific maps in the human brain. Our results encourage the broader adoption and use of this new imaging approach for characterizing healthy and pathological tissues.

Mobile health for cardiovascular risk management after cardiac surgery: results of a sub-analysis of The Box 2.0 study.

Aims: Lowering low-density lipoprotein (LDL-C) and blood pressure (BP) levels to guideline recommended values reduces the risk of major adverse cardiac events in patients who underwent coronary artery bypass grafting (CABG). To improve cardiovascular risk management, this study evaluated the effects of mobile health (mHealth) on BP and cholesterol levels in patients after standalone CABG. Methods and results: This study is a post hoc analysis of an observational cohort study among 228 adult patients who underwent standalone CABG surgery at a tertiary care hospital in The Netherlands. A total of 117 patients received standard care, and 111 patients underwent an mHealth intervention. This consisted of frequent BP and weight monitoring with regimen adjustment in case of high BP. Primary outcome was difference in systolic BP and LDL-C between baseline and value after three months of follow-up. Mean age in the intervention group was 62.7 years, 98 (88.3%) patients were male. A total of 26 449 mHealth measurements were recorded. At three months, systolic BP decreased by 7.0 mmHg [standard deviation (SD): 15.1] in the intervention group vs. -0.3 mmHg (SD: 17.6; P < 0.00001) in controls; body weight decreased by 1.76 kg (SD: 3.23) in the intervention group vs. -0.31 kg (SD: 2.55; P = 0.002) in controls. Serum LDL-C was significantly lower in the intervention group vs. controls (median: 1.8 vs. 2.0 mmol/L; P = 0.0002). Conclusion: This study showed an association between home monitoring after CABG and a reduction in systolic BP, body weight, and serum LDL-C. The causality of the association between the observed weight loss and decreased LDL-C in intervention group patients remains to be investigated.

Correlation Consistent Basis Sets for Explicitly Correlated Theory: The Transition Metals.

We present correlation consistent basis sets for explicitly correlated (F12) calculations, denoted VnZ(-PP)-F12-wis (n = D,T), for the d-block elements. The cc-pVDZ-F12-wis basis set is contracted to [8s7p5d2f] for the 3d-block, while its ECP counterpart for the 4d and 5d-blocks, cc-pVDZ-PP-F12-wis, is contracted to [6s6p5d2f]. The corresponding contracted sizes for cc-pVTZ(-PP)-F12-wis are [9s8p6d3f2g] for the 3d-block elements and [7s7p6d3f2g] for the 4d and 5d-block elements. Our VnZ(-PP)-F12-wis basis sets are evaluated on challenging test sets for metal-organic barrier heights (MOBH35) and group-11 metal clusters (CUAGAU-2). In F12 calculations, they are found to be about as close to the complete basis set limit as the combination of standard cc-pVnZ-F12 on main-group elements with the standard aug-cc-pV(n+1)Z(-PP) basis sets on the transition metal(s). While our basis sets are somewhat more compact than aug-cc-pV(n+1)Z(-PP), the CPU time benefit is negligible for catalytic complexes that contain only one or two transition metals among dozens of main-group elements; however, it is somewhat more significant for metal clusters.

Efficacy of IV Valproic Acid and Oral Valproic Acid Tapers for the Treatment of Pediatric Headaches in the Emergency Department.

Background and Objectives: Pediatric headaches, including migraine, are a common reason for emergency department (ED) presentation. IV valproic acid (VPA) followed by oral VPA tapers are often used to abort pediatric headache and reduce recurrence, though limited data exist regarding this approach. This study evaluated the effectiveness of IV VPA and oral VPA tapers for the treatment of acute pediatric headaches in the ED in preventing return encounters. Methods: This is a retrospective cohort study of patients aged 5-21 years presenting to a tertiary-care pediatric ED from 2010 to 2016 who received IV VPA for headache or migraine. Primary outcomes were ED disposition, percent pain reduction (initial vs 2-hour patient-reported pain score [10-point scale]), and return for acute headache treatment within 1 month. Results: A total of 486 ED encounters were included with a median patient age of 15 years; most of them were females (76%, 369/486). Of available pain scores within 2 hours of IV VPA administration, 41% (173/425) had ≥50% pain reduction. Fifty-two percent (254/486) were discharged without additional treatment, 14% (69/486) were discharged after additional treatment, and 33% (163/486) were admitted to the hospital. Initial pain score, number of preceding home treatments, and number of preceding ED treatments were not associated with ED disposition. Oral VPA tapers were prescribed in 39% (94/253) of encounters when the patient was discharged after IV VPA. Oral VPA tapers produced a transient decrease in recurrence at 72 hours, which was no longer present at 1 week nor 1 month. There was no difference in the time to recurrence or total number of return visits within 1 month. Discussion: IV VPA was efficacious in treating pediatric headaches evaluated in the ED, with nearly two-thirds of patients discharged home after administration. Oral VPA tapers did not reduce total headache recurrence nor time to recurrence. Given the limited benefit of oral VPA tapers, this practice should be re-examined. Classification of Evidence: This study provides Class IV evidence that for children with headache seen in the ED, IV VPA reduces head pain and Class III evidence that following this with an oral VPA taper is of no benefit.

Development and Evaluation of a Child Neurology Resident Curriculum for Communication Around Serious Illness.

Background: Communication around serious illness is a core competency for all residencies. One-fifth of neurology residencies have no curriculum. Published curricula use didactics or role-play to assess confidence performing this skill without evaluation in clinical settings. The SPIKES mnemonic (Setting, Perception, Invitation, Knowledge, Empathy, Strategy/Summary) outlines 6 evidence-based steps for communication around serious illness. It is unknown whether child neurology residents can incorporate SPIKES into communication around serious illness in clinical settings. Objective: To develop and evaluate a curriculum on communication around serious illness using SPIKES for child neurology residents that shows long-term skill retention in clinical settings at a single institution. Methods: In 2019, we created a pre-post survey and skills checklist based on SPIKES, with 20 total including 10 core skills. Faculty observed residents' (n = 7) communication with families and completed both preintervention and postintervention checklists for comparison. Residents underwent training in SPIKES during a 2-hour session using didactic and coached role-play. Results: All (n = 7) residents completed preintervention surveys, 4 of 6 completed postintervention. All (n = 6) participated in the training session. Following the training, 75% of residents reported improved confidence in use of SPIKES, though 50% were still unsure about appropriately responding to emotions. There was improvement in all SPIKES skills, with significant improvement in 6 of 20 skills up to 1 year following training. Conclusion: This is the first evaluation of the implementation of a communication around serious illness curriculum for child neurology residents. We identified improved comfort with SPIKES after training. Successful acquisition and utilization of this framework in our program suggests it could be incorporated into any residency program.

Corrigendum: The functional trajectory in frail compared with non-frail critically ill patients during the hospital stay.

[This corrects the article DOI: 10.3389/fmed.2021.748812.].

A double-hybrid density functional based on good local physics with outstanding performance on the GMTKN55 database.

In two recent papers [A. D. Becke, J. Chem. Phys. 156, 214101 (2022) and A. D. Becke, J. Chem. Phys. 157, 234102 (2022)], we compared two Kohn-Sham density functionals based on physical modeling and theory with the best density-functional power-series fits in the literature. The best error statistics reported to date for a hybrid functional on the general main-group thermochemistry, kinetics, and noncovalent interactions (GMTKN55) chemical database of Goerigk et al. [Phys. Chem. Chem. Phys. 19, 32184 (2017)] were obtained. In the present work, additional second-order perturbation-theory terms are considered. The result is a 12-parameter double-hybrid density functional with the lowest GMTKN55 WTMAD2 "weighted total mean absolute deviation" error (1.76 kcal/mol) yet seen for any hybrid or double-hybrid density-functional approximation. We call it "DH23."

The Importance of Tight f Basis Functions for Heavy p-Block Oxides and Halides: A Parallel With Tight d functions in the Second Row.

It is well-known that both wave function ab initio and DFT calculations on second-row compounds exhibit anomalously slow basis set convergence unless the basis sets are augmented with additional "tight" (high-exponent) d functions, as in the cc-pV(n+d)Z and aug-cc-pV(n+d)Z basis sets. This has been rationalized as being necessary for a better description of the low-lying 3d orbital, which as the oxidation state increases sinks low enough to act as a back-donation acceptor from chalcogen and halogen lone pairs. This prompts the question whether a similar phenomenon exists for the isovalent compounds of the heavy p-block. We show that for the fourth and fifth row, this is the case, but this time for tight f functions enhancing the description of the low-lying 4f and 5f Rydberg orbitals, respectively. In the third-row heavy p block, the 4f orbitals are too far up, while the 4d orbitals are adequately covered by the basis functions already present to describe the 3d subvalence orbitals.

Quantitative FIB/SEM tomogram analysis of closed and open porosity of spheroidized graphite anode materials for LiBs applications.

The electrochemical behaviour of rounded graphite particles as anode material in a lithium-ion battery strongly depends on the particle properties. The spheroidization process directly affects these properties, including the open porosity that determines the extent of direct contact between liquid electrolyte and carbon surface. Therefore, the quantification of the proportion between open and closed pores is of great interest. Here, we quantify the open and closed porosity of spheroidized porous graphite particles from FIB-SEM tomograms. Quantification is achieved based on two developments: (1) a new sample preparation strategy and (2) a newly developed image evaluation scheme based on neural networks. The sample preparation strategy involves embedding of many graphite powder particles in indium enabling the investigation of several graphite particles in one FIB/SEM tomogram with high stability and with high contrast between the conductive embedding material and porous graphite. A quantitative evaluation of closed and open porosity is achieved by machine learning in form of convolutional neural networks. The convolutional neural network is used to detect the bulk graphite and by further morphological operations, closed and open pores are identified. An error is determined by comparing automatically created quantifications with manual reference values. Our porosity data for two differently spheroidized graphite samples agree qualitatively well with corresponding results from nitrogen physisorption measurements. This approach may allow quantitative data evaluation from porous powders and support understanding of the correlation to the electrochemical behaviour in the lithium-ion battery.

Mobile health vs. standard care after cardiac surgery: results of The Box 2.0 study.

AIMS: Postoperative atrial fibrillation (POAF) is a common complication of cardiac surgery, yet difficult to detect in ambulatory patients. The primary aim of this study is to investigate the effect of a mobile health (mHealth) intervention on POAF detection after cardiac surgery. METHODS AND RESULTS: We performed an observational cohort study among 730 adult patients who underwent cardiac surgery at a tertiary care hospital in The Netherlands. Of these patients, 365 patients received standard care and were included as a historical control group, undergoing surgery between December 2017 and September 2018, and 365 patients were prospectively included from November 2018 and November 2020, undergoing an mHealth intervention which consisted of blood pressure, temperature, weight, and electrocardiogram (ECG) monitoring. One physical outpatient follow-up moment was replaced by an electronic visit. All patients were requested to fill out a satisfaction and quality of life questionnaire. Mean age in the intervention group was 62 years, 275 (70.4%) patients were males. A total of 4136 12-lead ECGs were registered. In the intervention group, 61 (16.7%) patients were diagnosed with POAF vs. 25 (6.8%) patients in the control group [adjusted risk ratio (RR) of POAF detection: 2.15; 95% confidence interval (CI): 1.55-3.97]. De novo atrial fibrillation was found in 13 patients using mHealth (6.5%) vs. 4 control group patients (1.8%; adjusted RR 3.94, 95% CI: 1.50-11.27). CONCLUSION: Scheduled self-measurements with mHealth devices could increase the probability of detecting POAF within 3 months after cardiac surgery. The effect of an increase in POAF detection on clinical outcomes needs to be addressed in future research.

Performance of Localized-Orbital Coupled-Cluster Approaches for the Conformational Energies of Longer n-Alkane Chains.

We report an update and enhancement of the ACONFL (conformer energies of large alkanes [J. Phys. Chem. A2022,126, 3521-3535]) dataset. For the ACONF12 (n-dodecane) subset, we report basis set limit canonical coupled-cluster with singles, doubles, and perturbative triples [i.e., CCSD(T)] reference data obtained from the MP2-F12/cc-pV{T,Q}Z-F12 extrapolation, [CCSD(F12*)-MP2-F12]/aug-cc-pVTZ-F12, and a (T) correction from conventional CCSD(T)/aug-cc-pV{D,T}Z calculations. Then, we explored the performance of a variety of single and composite localized-orbital CCSD(T) approximations, ultimately finding an affordable localized natural orbital CCSD(T) [LNO-CCSD(T)]-based post-MP2 correction that agrees to 0.006 kcal/mol mean absolute deviation with the revised canonical reference data. In tandem with canonical MP2-F12 complete basis set extrapolation, this was then used to re-evaluate the ACONF16 and ACONF20 subsets for n-hexadecane and n-icosane, respectively. Combining those with the revised canonical reference data for the dodecane conformers (i.e., ACONF12 subset), a revised ACONFL set was obtained. It was then used to assess the performance of different localized-orbital coupled-cluster approaches, such as pair natural orbital localized CCSD(T) [PNO-LCCSD(T)] as implemented in MOLPRO, DLPNO-CCSD(T0) and DLPNO-CCSD(T1) as implemented in ORCA, and LNO-CCSD(T) as implemented in MRCC, at their respective "Normal", "Tight", "vTight", and "vvTight" accuracy settings. For a given accuracy threshold and basis set, DLPNO-CCSD(T1) and DLPNO-CCSD(T0) perform comparably. With "VeryTightPNO" cutoffs, explicitly correlated DLPNO-CCSD(T1)-F12/VDZ-F12 is the best pick among all the DLPNO-based methods tested. To isolate basis set incompleteness from localized-orbital-related truncation errors (domain, LNOs), we have also compared the localized coupled-cluster approaches with canonical DF-CCSD(T)/aug-cc-pVTZ for the ACONF12 set. We found that gradually tightening the cutoffs improves the performance of LNO-CCSD(T), and using a composite scheme such as vTight + 0.50[vTight - Tight] improves things further. For DLPNO-CCSD(T1), "TightPNO" and "VeryTightPNO" offer a statistically similar accuracy, which gets slightly better when TCutPNO is extrapolated to the complete PNO space limit. Similar to Brauer et al.'s [Phys. Chem. Chem. Phys.2016,18 (31), 20905-20925] previous report for the S66x8 noncovalent interactions, the dispersion-corrected direct random phase approximation (dRPA)-based double hybrids perform remarkably well for the ACONFL set. While the revised reference data do not affect any conclusions on the less accurate methods, they may upend orderings for more accurate methods with error statistics on the same order as the difference between reference datasets.

A standardised methodology for the extraction and quantification of cell-free DNA in cerebrospinal fluid and application to evaluation of Alzheimer's disease and brain cancers.

Cerebrospinal fluid (CSF) is a source of diagnostic biomarkers for a range of neurological conditions. Cell-free DNA (cfDNA) is detected in CSF and differences in the concentration of cell-free mitochondrial DNA have been reported in studies of neurodegenerative disorders including Alzheimer's disease (AD). However, the influence of pre-analytical steps has not been investigated for cfDNA in CSF and there is no standardised approach for quantification of total cfDNA (copies of nuclear genome or mitochondria-derived gene targets). In this study, the suitability of four extraction methods was evaluated: QIAamp Circulating Nucleic Acid (Qiagen), Quick-cfDNA Serum & Plasma (Zymo), NucleoSnap® DNA Plasma (Macherey-Nagel) and Plasma/Serum Circulating DNA Purification Mini (Norgen) kits, for cfDNA extraction from CSF of controls and AD dementia patients, utilising a spike-in control for extraction efficiency and fragment size. One of the optimal extraction methods was applied to a comparison of cfDNA concentrations in CSF from control subjects, AD dementia and primary and secondary brain tumour patients. Extraction efficiency based on spike-in recovery was similar in all three groups whilst both endogenous mitochondrial and nucleus-derived cfDNA was significantly higher in CSF from cancer patients compared to control and AD groups, which typically contained < 100 genome copies/mL. This study shows that it is feasible to measure low concentration nuclear and mitochondrial gene targets in CSF and that normalisation of extraction yield can help control pre-analytical variability influencing biomarker measurements.

S66x8 noncovalent interactions revisited: new benchmark and performance of composite localized coupled-cluster methods.

The S66x8 noncovalent interactions benchmark has been re-evaluated at the "sterling silver" level, using explicitly correlated MP2-F12 near the complete basis set limit, CCSD(F12*)/aug-cc-pVTZ-F12, and a (T) correction from conventional CCSD(T)/sano-V{D,T}Z+ calculations. The revised reference values differ by 0.1 kcal mol-1 RMS from the original Hobza benchmark and its revision by Brauer et al., but by only 0.04 kcal mol-1 RMS from the "bronze" level data in Kesharwani et al., Aust. J. Chem., 2018, 71, 238-248. We then used these to assess the performance of localized-orbital coupled cluster approaches with and without counterpoise corrections, such as PNO-LCCSD(T) as implemented in MOLPRO, DLPNO-CCSD(T1) as implemented in ORCA, and LNO-CCSD(T) as implemented in MRCC, for their respective "Normal", "Tight", and "very Tight" settings. We also considered composite approaches combining different basis sets and cutoffs. Furthermore, in order to isolate basis set convergence from domain truncation error, for the aug-cc-pVTZ basis set we compared PNO, DLPNO, and LNO approaches with canonical CCSD(T). We conclude that LNO-CCSD(T) with veryTight criteria performs very well for "raw" (CP-uncorrected), but struggles to reproduce counterpoise-corrected numbers even for veryveryTight criteria: this means that accurate results can be obtained using either extrapolation from basis sets large enough to quench basis set superposition error (BSSE) such as aug-cc-pV{Q,5}Z, or using a composite scheme such as Tight{T,Q} + 1.11[vvTight(T) - Tight(T)]. In contrast, PNO-LCCSD(T) works best with counterpoise, while performance with and without counterpoise is comparable for DLPNO-CCSD(T1). Among more economical methods, the highest accuracies are seen for dRPA75-D3BJ, ωB97M-V, ωB97M(2), revDSD-PBEP86-D4, and DFT(SAPT) with a TDEXX or ATDEXX kernel.

Explicitly Correlated Double-Hybrid DFT: A Comprehensive Analysis of the Basis Set Convergence on the GMTKN55 Database.

Double-hybrid density functional theory (DHDFT) offers a pathway to accuracy approaching composite wavefunction approaches such as G4 theory. However, the Görling-Levy second-order perturbation theory (GLPT2) term causes them to partially inherit the slow ∝L-3 (with L the maximum angular momentum) basis set convergence of correlated wavefunction methods. This could potentially be remedied by introducing F12 explicit correlation: we investigate the basis set convergence of both DHDFT and DHDFT-F12 (where GLPT2 is replaced by GLPT2-F12) for the large and chemically diverse general main-group thermochemistry, kinetics, and noncovalent interactions (GMTKN55) benchmark suite. The B2GP-PLYP-D3(BJ) and revDSD-PBEP86-D4 DHDFs are investigated as test cases, together with orbital basis sets as large as aug-cc-pV5Z and F12 basis sets as large as cc-pVQZ-F12. We show that F12 greatly accelerates basis set convergence of DHDFs, to the point that even the modest cc-pVDZ-F12 basis set is closer to the basis set limit than cc-pV(Q+d)Z or def2-QZVPPD in orbital-based approaches, and in fact comparable in quality to cc-pV(5+d)Z. Somewhat surprisingly, aug-cc-pVDZ-F12 is not required even for the anionic subsets. In conclusion, DHDF-F12/VDZ-F12 eliminates concerns about basis set convergence in both the development and applications of double-hybrid functionals. Mass storage and I/O bottlenecks for larger systems can be circumvented by localized pair natural orbital approximations, which also exhibit much gentler system size scaling.

Reduced-Scaling Double Hybrid Density Functional Theory with Rapid Basis Set Convergence through Localized Pair Natural Orbital F12.

Following earlier work [Mehta, N.; Martin, J. M. L. J. Chem. Theory Comput.2022, 10.1021/acs.jctc.2c00426] that showed how the slow basis set convergence of the double hybrid density functional theory can be obviated by the use of F12 explicit correlation in the GLPT2 step (second order Görling-Levy perturbation theory), we demonstrate here for the very large and chemically diverse GMTKN55 benchmark suite that the CPU time scaling of this step can be reduced (asymptotically linearized) using the localized pair natural orbital (PNO-L) approximation at negligible cost in accuracy.

Anterior Pituitary Hormones in Blood and Cerebrospinal Fluid of Patients in Neurocritical Care.

BACKGROUND: Anterior pituitary hormones in blood follow a circadian rhythm, which may be influenced by various factors such as intracranial pathologies. In cerebrospinal fluid (CSF), pituitary hormones have been collected only selectively and circadian rhythm has not yet been investigated. This pilot study analysed diurnal variations of anterior pituitary hormones in patients in neurocritical care to determine whether circadian rhythmicity exists in these patients. Possible influences of intracranial pathologies were also investigated. Blood and CSF concentrations were assessed simultaneously to explore the value of blood concentrations as a surrogate parameter for CSF levels. METHODS: Blood and CSF samples of 20 non-sedated patients were collected at 06:00, noon, 18:00 and midnight, and analysed for adrenocorticotropic hormone (ACTH), cortisol, thyroid-stimulating hormone (TSH) and insulin-like growth factor-1 (IGF-1) concentrations at each of the four time points. ACTH and IGF-1 were measured by sandwich chemiluminescence immunoassay. Cortisol and TSH were measured by electrochemiluminescence immunoassay. RESULTS: Results showed inconsistent circadian rhythms. Less than 50% of the patients showed a circadian rhythmicity of ACTH, cortisol, TSH or IGF-1. Significance of diurnal variations was only present for blood concentrations of TSH. Correlations between blood and CSF concentrations were strong for cortisol and TSH. CONCLUSIONS: CSF concentrations were only in the measurable range in some of the patients. No clear circadian rhythmicity could be identified, except for TSH in blood. Absence of significant diurnal variations could be explained by the underlying pathologies or disturbing influences of the intensive care unit. Blood concentrations of cortisol and TSH may be suitable surrogate parameters for CSF.