Progressive Brain Atrophy in Multiple System Atrophy: A Longitudinal, Multicenter, Magnetic Resonance Imaging Study.

OBJECTIVE: To determine the rates of brain atrophy progression in vivo in patients with multiple system atrophy (MSA). BACKGROUND: Surrogate biomarkers of disease progression are a major unmet need in MSA. Small-scale longitudinal studies in patients with MSA using magnetic resonance imaging (MRI) to assess progression of brain atrophy have produced inconsistent results. In recent years, novel MRI post-processing methods have been developed enabling reliable quantification of brain atrophy in an automated fashion. METHODS: Serial 3D-T1-weighted MRI assessments (baseline and after 1 year of follow-up) of 43 patients with MSA were analyzed and compared to a cohort of early-stage Parkinson's disease (PD) patients and healthy controls (HC). FreeSurfer's longitudinal analysis stream was used to determine the brain atrophy rates in an observer-independent fashion. RESULTS: Mean ages at baseline were 64.4 ± 8.3, 60.0 ± 7.5, and 59.8 ± 9.2 years in MSA, PD patients and HC, respectively. A mean disease duration at baseline of 4.1 ± 2.5 years in MSA patients and 2.3 ± 1.4 years in PD patients was observed. Brain regions chiefly affected by MSA pathology showed progressive atrophy with annual rates of atrophy for the cerebellar cortex, cerebellar white matter, pons, and putamen of -4.24 ± 6.8%, -8.22 ± 8.8%, -4.67 ± 4.9%, and - 4.25 ± 4.9%, respectively. Similar to HC, atrophy rates in PD patients were minimal with values of -0.41% ± 1.8%, -1.47% ± 4.1%, -0.04% ± 1.8%, and -1.54% ± 2.2% for cerebellar cortex, cerebellar white matter, pons, and putamen, respectively. CONCLUSIONS: Patients with MSA show significant brain volume loss over 12 months, and cerebellar, pontine, and putaminal volumes were the most sensitive to change in mid-stage disease. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Deutetrabenazine Provides Long-Term Benefit for Tardive Dyskinesia Regardless of Underlying Condition and Dopamine Receptor Antagonist Use: A Post Hoc Analysis of the 3-Year, Open-Label Extension Study.

BACKGROUND: Deutetrabenazine is approved for adults with tardive dyskinesia (TD). Data based on underlying psychiatric condition and baseline dopamine receptor antagonist (DRA) use are limited. METHODS: Patients with TD who completed parent studies ARM-TD or AIM-TD were eligible for the 3-year, open-label extension study (RIM-TD; NCT02198794). In RIM-TD, deutetrabenazine was titrated based on dyskinesia control and tolerability. In this post hoc analysis of RIM-TD, total motor Abnormal Involuntary Movement Scale (AIMS) score and adverse events (AEs) were analyzed by underlying condition and DRA use at parent study baseline. RESULTS: Of 343 patients enrolled in RIM-TD, 336 were included in the analysis by underlying condition, and 337 were included in the analysis by DRA use. One hundred eighty-nine of 205 (92%) patients with psychotic disorders (schizophrenia/schizoaffective disorder) and 65 of 131 (50%) with mood and other disorders (depression/bipolar disorder/other) were receiving a DRA. Mean (SE) deutetrabenazine doses at week 145 were 40.4 (1.13), 38.5 (1.21), 39.9 (1.00), and 38.5 (1.48) mg/d for patients with psychotic disorders, those with mood and other disorders, and those receiving DRAs or not, respectively. Mean (SD) changes in total motor AIMS score from this study baseline to week 145 were -6.3 (4.53), -7.1 (4.92), -6.1 (4.42), and -7.5 (5.19). Exposure-adjusted incidence rates (number of AEs/patient-years) of AEs were similar across groups: any (1.02, 1.71, 1.08, 1.97), serious (0.10, 0.12, 0.10, 0.12), and leading to discontinuation (0.07, 0.05, 0.06, 0.05). CONCLUSIONS: Long-term deutetrabenazine provided clinically meaningful improvements in TD-related movements, with a favorable benefit-risk profile, regardless of underlying condition or DRA use.

R-8 Dispersion Interaction: Derivation and Application to the Effective Fragment Potential Method.

The anisotropic and isotropic R-8 dispersion contributions (disp8) are derived and implemented within the framework of the effective fragment potential (EFP) method formulated with imaginary frequency-dependent Cartesian polarizability tensors distributed at the centroids of the localized molecular orbitals (LMOs). Two forms of damping functions, intermolecular overlap-based and Tang-Toennies, are extended for disp8. To obtain LMO polarizability tensors centered at LMO centroids, an origin-shifting transformation is derived and implemented for the dipole-octopole polarizability tensor and the quadrupole-quadrupole polarizability tensor. The analytic gradient is derived and implemented for the isotropic disp8 contribution. Relative to the previously implemented empirical EFP disp8 energy, the isotropic disp8 component of the interaction energy improves the overall agreement of the EFP dispersion energies with the symmetry-adapted perturbation theory (SAPT) benchmarks, reducing the mean absolute errors (MAEs) and mean absolute percentage errors for most of the databases examined in this work. While the anisotropic disp8 can further enhance the accuracy of the EFP dispersion energy and yield smaller MAEs, significantly overbound dispersion energies are predicted by the anisotropic disp8 when the maximum element in the intermolecular overlap matrix is greater than 0.1, possibly due to the breakdown of the approximations made in the EFP dispersion derivation at a short range. For potential energy scan databases, the newly developed EFP dispersion model with isotropic disp8 yields the overall correct curvature and good agreement with SAPT benchmarks around equilibrium and longer but overestimates the dispersion interactions at a short range. While the overlap-based dispersion-damping functions produce better MAEs than Tang-Toennies damping functions, further improvement is needed to better screen the large attractive dispersion energies at a short range (overlap >0.1).

Prediction of stability constants of metal-ligand complexes by machine learning for the design of ligands with optimal metal ion selectivity.

The new LOGKPREDICT program integrates HostDesigner molecular design software with the machine learning (ML) program Chemprop. By supplying HostDesigner with predicted log K values, LOGKPREDICT enhances the computer-aided molecular design process by ranking ligands directly by metal-ligand binding strength. Harnessing reliable experimental data from a historic National Institute of Standards and Technology (NIST) database and data from the International Union of Pure and Applied Chemistry (IUPAC), we train message passing neural net algorithms. The multi-metal NIST-based ML model has a root mean square error (RMSE) of 0.629 ± 0.044 (R2 of 0.960 ± 0.006), while two versions of lanthanide-only IUPAC-based ML models have, respectively, RMSE of 0.764 ± 0.073 (R2 of 0.976 ± 0.005) and 0.757 ± 0.071 (R2 of 0.959 ± 0.007). For relative log K predictions on an out-of-sample set of six ligands, demonstrating metal ion selectivity, the RMSE value reaches a commendably low 0.25. We showcase the use of LOGKPREDICT in identifying ligands with high selectivity for lanthanides in aqueous solutions, a finding supported by recent experimental evidence. We also predict new ligands yet to be verified experimentally. Therefore, our ML models implemented through LOGKPREDICT and interfaced with the ligand design software HostDesigner pave the way for designing new ligands with predetermined selectivity for competing metal ions in an aqueous solution.

Analysis of the bonding in tetrahedrane and phosphorus-substituted tetrahedranes.

The bonding structures of tetrahedrane, phosphatetrahedrane, diphosphatetrahedrane and triphosphatetrahedrane are studied by employing an intrinsic quasi-atomic orbital analysis. Ethane, cyclopropane and tetrahedral P4 are employed as reference systems. The orbital analysis is paired with the computation of strain energies via isodesmic reactions. The results show that the increase in geometric strain upon transition from ethane to cyclopropane to tetrahedrane weakens the CC bonds, despite leading to shorter C-C interatomic distances. With the increase in strain, the orbitals centered on C and involved in the bonding of the cage structure are observed to have elevated p-character, and the orbital structure of C deviates from sp3 hybridization. The systematic substitution of CH groups by P atoms in the cage structure of tetrahedrane leads to stronger CC bonds, larger angles in the cage structures of the resulting phosphatetrahedranes, lower p-character in the orbitals involved in the bonding of the cages, and lower strain energies. It is found that P is more amenable to strained molecular arrangements than is C, and that the propensity of a given atom to hybridize s and p functions, or the lack thereof, has implications in the stability of molecules with strained geometries. The combination of the calculations presented here with the existing literature provides insight into the apparent propensity of tetrahedrane and P4 to 'break' their tetrahedral structures. Trends in the bonding interactions, such as bond strengths, s- and p-orbital characters and charge transfer are identified and related to the strain energy observed in each of the analyzed systems.

Intermolecular interactions in clusters of ethylammonium nitrate and 1-amino-1,2,3-triazole.

The intermolecular interaction energies, including hydrogen bonds (H-bonds), of clusters of the ionic liquid ethylammonium nitrate (EAN) and 1-amino-1,2,3-triazole (1-AT) based deep eutectic propellants (DeEP) are examined. 1-AT is introduced as a neutral hydrogen bond donor (HBD) to EAN in order to form a eutectic mixture. The effective fragment potential (EFP) is used to examine the bonding interactions in the DeEP clusters. The resolution of the Identity (RI) approximated second order Møller-Plesset perturbation theory (RI-MP2) and coupled cluster theory (RI-CCSD(T)) are used to validate the EFP results. The EFP method predicts that there are significant polarization and charge transfer effects in the EAN:1-AT complexes, along with Coulombic, dispersion and exchange repulsion interactions. The EFP interaction energies are in good agreement with the RI-MP2 and RI-CCSD(T) results. The quasi-atomic orbital (QUAO) bonding and kinetic bond order (KBO) analyses are additionally used to develop a conceptual and semi-quantitative understanding of the H-bonding interactions as a function of the size of the system. The QUAO and KBO analyses suggest that the H-bonds in the examined clusters follow the characteristic hydrogen bonding three-center four electron interactions. The strongest H-bonding interactions between the (EAN)1:(1-AT)n and (EAN)2:(1-AT)n (n = 1-5) complexes are observed internally within EAN; that is, between the ethylammonium cation [EA]+ and the nitrate anion ([NO3]-). The weakest H-bonding interactions occur between [NO3]- and 1-AT. Consequently, the average strengths of the H-bonds within a given (EAN)x:(1-AT)n complex decrease as more 1-AT molecules are introduced into the EAN monomer and EAN dimer. The QUAO bonding analysis suggests that 1-AT in (EAN)x:(1-AT)n can act as both a HBD and a hydrogen bond acceptor simultaneously. It is observed that two 1-AT molecules can form H-bonds to each other. Although the KBOs that correspond to H-bonding interactions in [EA]+:1-AT, [NO3]-:1-AT and between two 1-AT molecules are weaker than the H-bonds in EAN, those weak H-bond networks with 1-AT could be important to form a stable DeEP.

Quantum Chemical Modeling of Propellant Degradation.

An ab initio quantum chemical approach for the modeling of propellant degradation is presented. Using state-of-the-art bonding analysis techniques and composite methods, a series of potential degradation reactions are devised for a sample hydroxyl-terminated-polybutadiene (HTPB) type solid fuel. By applying thermochemical procedures and isodesmic reactions, accurate thermochemical quantities are obtained using a modified G3 composite method based on the resolution of the identity. The calculated heats of formation for the different structures produced presents an ∼2 kcal/mol average error when compared against experimental values.

High-performance strategies for the recent MRSF-TDDFT in GAMESS.

Multiple ERI (Electron Repulsion Integral) tensor contractions (METC) with several matrices are ubiquitous in quantum chemistry. In response theories, the contraction operation, rather than ERI computations, can be the major bottleneck, as its computational demands are proportional to the multiplicatively combined contributions of the number of excited states and the kernel pre-factors. This paper presents several high-performance strategies for METC. Optimal approaches involve either the data layout reformations of interim density and Fock matrices, the introduction of intermediate ERI quartet buffer, and loop-reordering optimization for a higher cache hit rate. The combined strategies remarkably improve the performance of the MRSF (mixed reference spin flip)-TDDFT (time-dependent density functional theory) by nearly 300%. The results of this study are not limited to the MRSF-TDDFT method and can be applied to other METC scenarios.

Spin-orbit coupling of electrons on separate lanthanide atoms of Pr2O2 and its singly charged cation.

Although it plays a critical role in the photophysics and catalysis of lanthanides, spin-orbit coupling of electrons on individual lanthanide atoms in small clusters is not well understood. The major objective of this work is to probe such coupling of the praseodymium (Pr) 4f and 6s electrons in Pr2O2 and Pr2O2+. The approach combines mass-analyzed threshold ionization spectroscopy and spin-orbit multiconfiguration second-order quasi-degenerate perturbation theory. The energies of six ionization transitions are precisely measured; the adiabatic ionization energy of the neutral cluster is 38 045 (5) cm-1. Most of the electronic states involved in these transitions are identified as spin-orbit coupled states consisting of two or more electron spins. The electron configurations of these states are 4f46s2 for the neutral cluster and 4f46s for the singly charged cation, both in planar rhombus-type structures. The spin-orbit splitting due to the coupling of the electrons on the separate Pr atoms is on the order of hundreds of wavenumbers.

Porting fragmentation methods to GPUs using an OpenMP API: Offloading the resolution-of-the-identity second-order Møller-Plesset perturbation method.

Using an OpenMP Application Programming Interface, the resolution-of-the-identity second-order Møller-Plesset perturbation (RI-MP2) method has been off-loaded onto graphical processing units (GPUs), both as a standalone method in the GAMESS electronic structure program and as an electron correlation energy component in the effective fragment molecular orbital (EFMO) framework. First, a new scheme has been proposed to maximize data digestion on GPUs that subsequently linearizes data transfer from central processing units (CPUs) to GPUs. Second, the GAMESS Fortran code has been interfaced with GPU numerical libraries (e.g., NVIDIA cuBLAS and cuSOLVER) for efficient matrix operations (e.g., matrix multiplication, matrix decomposition, and matrix inversion). The standalone GPU RI-MP2 code shows an increasing speedup of up to 7.5× using one NVIDIA V100 GPU with one IBM 42-core P9 CPU for calculations on fullerenes of increasing size from 40 to 260 carbon atoms using the 6-31G(d)/cc-pVDZ-RI basis sets. A single Summit node with six V100s can compute the RI-MP2 correlation energy of a cluster of 175 water molecules using the correlation consistent basis sets cc-pVDZ/cc-pVDZ-RI containing 4375 atomic orbitals and 14 700 auxiliary basis functions in ∼0.85 h. In the EFMO framework, the GPU RI-MP2 component shows near linear scaling for a large number of V100s when computing the energy of an 1800-atom mesoporous silica nanoparticle in a bath of 4000 water molecules. The parallel efficiencies of the GPU RI-MP2 component with 2304 and 4608 V100s are 98.0% and 96.1%, respectively.

Toward an extreme-scale electronic structure system.

Electronic structure calculations have the potential to predict key matter transformations for applications of strategic technological importance, from drug discovery to material science and catalysis. However, a predictive physicochemical characterization of these processes often requires accurate quantum chemical modeling of complex molecular systems with hundreds to thousands of atoms. Due to the computationally demanding nature of electronic structure calculations and the complexity of modern high-performance computing hardware, quantum chemistry software has historically failed to operate at such large molecular scales with accuracy and speed that are useful in practice. In this paper, novel algorithms and software are presented that enable extreme-scale quantum chemistry capabilities with particular emphasis on exascale calculations. This includes the development and application of the multi-Graphics Processing Unit (GPU) library LibCChem 2.0 as part of the General Atomic and Molecular Electronic Structure System package and of the standalone Extreme-scale Electronic Structure System (EXESS), designed from the ground up for scaling on thousands of GPUs to perform high-performance accurate quantum chemistry calculations at unprecedented speed and molecular scales. Among various results, we report that the EXESS implementation enables Hartree-Fock/cc-pVDZ plus RI-MP2/cc-pVDZ/cc-pVDZ-RIFIT calculations on an ionic liquid system with 623 016 electrons and 146 592 atoms in less than 45 min using 27 600 GPUs on the Summit supercomputer with a 94.6% parallel efficiency.

Is the association between blood pressure and cognition in the oldest-old modified by physical, vascular or brain pathology markers? The EMIF-AD 90 + Study.

BACKGROUND: Prior studies suggest a changing association between blood pressure (BP) and cognition with aging, however work in the oldest-old has yielded ambiguous results. Potentially, these mixed results can be explained by modifying factors. The aim of this study was to establish whether physical, vascular or brain pathology markers that describe a state of increased vulnerability, affect the association between BP and cognition in the oldest-old. Results may influence clinicians' decisions regarding the use of antihypertensives in this age group. METHODS: We included 122 individuals (84 without cognitive impairment and 38 with cognitive impairment) from the EMIF-AD 90 + Study (mean age 92.4 years). First, we tested cross-sectional associations of systolic and diastolic BP with a cognitive composite score. Second, we tested whether these associations were modified by physical markers (waist circumference, muscle mass, gait speed and handgrip strength), vascular markers (history of cardiac disease, carotid intima media thickness as a proxy for atherosclerosis and carotid distensibility coefficient as a proxy for arterial stiffness) or brain pathology markers (white matter hyperintensities and cortical thickness). RESULTS: In the total sample, there was no association between BP and cognition, however, waist circumference modified this association (p-value for interaction with systolic BP: 0.03, with diastolic BP: 0.01). In individuals with a high waist circumference, higher systolic and diastolic BP tended to be associated with worse cognition, while in individuals with a low waist circumference, higher systolic BP was associated with better cognition. The others physical, vascular and brain pathology markers did not modify the association between BP and cognition. CONCLUSIONS: When examining various markers for physical, vascular and brain vulnerability, only waist circumference affected the association between BP and cognition. This warrants further research to evaluate whether waist circumference may be a marker in clinical practice influencing the use of antihypertensives in the oldest-old.

Sensitivity to Change and Patient-Centricity of the Unified Multiple System Atrophy Rating Scale Items: A Data-Driven Analysis.

BACKGROUND: The Unified Multiple System Atrophy Rating Scale (UMSARS) is a commonly used semiquantitative rating scale to assess symptoms and measure disease progression in multiple system atrophy (MSA). However, it is currently incompletely understood which UMSARS items are the most sensitive to change and most relevant to the patient. OBJECTIVE: The objective of this study was to assess sensitivity to change and patient-centricity of single UMSARS items. METHODS: Data were taken from the European Multiple System Atrophy Study Group Natural History Study and the Rasagiline for Multiple System Atrophy trial. Sensitivity of change of an item of the UMSARS was assessed by calculation of a sensitivity-to-change ratio using its mean slope of progression divided by the standard deviation of the slope when modeling its progression over time. Patient-centricity was assessed through correlation of UMSARS items with quality-of-life measures. RESULTS: Progression rates above the mean in at least one of the two studies examined here were seen for seven items of UMSARS I and 11 items of UMSARS II. These items related to key motor functions such as swallowing, speech, handwriting, cutting food, hygiene, and dressing or walking, whereas items related to autonomic dysfunction were generally less sensitive to change in either data set. More UMSARS I items were identified as patient-centric compared with UMSARS II items, and items most strongly impacting patients' quality of life were those affecting verbal communication skills, personal hygiene, and walking. CONCLUSION: The present results illustrate the potential to optimize the UMSARS to enhance sensitivity to change and patient centricity. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Long-Term Safety and Efficacy of Deutetrabenazine in Younger and Older Patients With Tardive Dyskinesia.

OBJECTIVES: To assess long-term safety and efficacy of deutetrabenazine in younger (<55 years) and older (≥55 years) adult participants with tardive dyskinesia (TD). DESIGN: Three-year, single-arm, open-label extension (OLE) study enrolling participants who completed the 12-week, pivotal ARM-TD or AIM-TD studies. SETTING: Seventy-six centers in the United States and Europe. PARTICIPANTS: A total of 337 participants with TD (119 younger and 218 older). INTERVENTION: Deutetrabenazine was initiated at 12 mg/day and titrated once weekly by 6 mg/day using a response-driven dosing regimen until adequate dyskinesia control was reached or a clinically significant adverse event occurred. MEASUREMENTS: This post hoc analysis assessed change and percent change from baseline in total motor Abnormal Involuntary Movement Scale (AIMS) score, response rates for ≥50% AIMS improvement, Clinical Global Impression of Change (CGIC), Patient Global Impression of Change (PGIC), and safety in younger and older participants with TD. RESULTS: After 3 years of open-label treatment, mean deutetrabenazine dose was ∼39.5 mg/day in both groups. Mean±SE changes from baseline in total motor AIMS score were -6.7 ± 0.62 and -6.5 ± 0.47 in younger and older participants, respectively (percent changes: -61.4% ± 4.10% and -54.6% ± 3.01%); 76% of younger and 62% of older participants achieved ≥50% AIMS response. Most younger and older participants achieved treatment success per CGIC (67% and 76%) and PGIC (64% and 63%). Deutetrabenazine was generally well tolerated in both groups. CONCLUSIONS: Deutetrabenazine treatment was associated with sustained improvements in total motor AIMS score, treatment success, and improved quality of life, and was well tolerated in younger and older adults with TD in this 3-year OLE study.

Many-Body Dispersion.

A broad range of approaches to many-body dispersion are discussed, including empirical approaches with multiple fitted parameters, augmented density functional-based approaches, symmetry adapted perturbation theory, and a supermolecule approach based on coupled cluster theory. Differing definitions of "body" are considered, specifically atom-based vs molecule-based approaches.

Molecular interactions in diffusion-controlled aldol condensation with mesoporous silica nanoparticles.

The aldol reaction of p-nitrobenzaldehyde in amino-catalyzed mesoporous silica nanoparticles (MSN) has revealed varying catalytic activity with the size of the pores of MSN. The pore size dependence related to the reactivity indicates that the diffusion process is important. A detailed molecular-level analysis for understanding diffusion requires assessment of the noncovalent interactions of the molecular species involved in the aldol reaction with each other, with the solvent, and with key functional groups on the pore surface. Such an analysis is presented here based upon the effective fragment potential (EFP). The EFP method can calculate the intermolecular interactions, decomposed into Coulomb, polarization, dispersion, exchange-repulsion, and charge-transfer interactions. In this study, the potential energy surfaces corresponding to each intermolecular interaction are analyzed for homo- and hetero-dimers with various configurations. The monomers that compose dimers are five molecules such as p-nitrobenzaldehyde, acetone, n-hexane, propylamine, and silanol. The results illustrate that the dispersion interaction is crucial in most dimers.

General, Rigorous Approach for the Treatment of Interfragment Covalent Bonds.

A generalized, projection-based transformation of the method-agnostic Fock operator in various ab initio fragment-based quantum chemistry methods has been developed for the treatment of interfragment covalent bonds. This transformation freezes the relevant localized molecular orbital associated with each interfragment bond, thereby restricting the variational subspace of the fragment wave functions, in order to maintain the proper physical characteristics of the involved covalent bonds. In addition, sets of orbitals that would lead to multiple occupancy of certain orbitals are explicitly removed from the variational space. The transformation is developed for the specific case of mutually orthonormal frozen and unfrozen orbitals within each fragment. The newly developed approach is then used to study model systems with two popular ab initio fragment-based methods, and the results of these calculations are compared to those obtained by existing methodologies. Analysis is focused on both quantitative and qualitative accuracy as well as computational scalability and stability. Other methods for which the developed formalisms are appropriate are outlined, and future extensions of the methods are discussed.

Oil sands operations as a large source of secondary organic aerosols.

Worldwide heavy oil and bitumen deposits amount to 9 trillion barrels of oil distributed in over 280 basins around the world, with Canada home to oil sands deposits of 1.7 trillion barrels. The global development of this resource and the increase in oil production from oil sands has caused environmental concerns over the presence of toxic compounds in nearby ecosystems and acid deposition. The contribution of oil sands exploration to secondary organic aerosol formation, an important component of atmospheric particulate matter that affects air quality and climate, remains poorly understood. Here we use data from airborne measurements over the Canadian oil sands, laboratory experiments and a box-model study to provide a quantitative assessment of the magnitude of secondary organic aerosol production from oil sands emissions. We find that the evaporation and atmospheric oxidation of low-volatility organic vapours from the mined oil sands material is directly responsible for the majority of the observed secondary organic aerosol mass. The resultant production rates of 45-84 tonnes per day make the oil sands one of the largest sources of anthropogenic secondary organic aerosols in North America. Heavy oil and bitumen account for over ten per cent of global oil production today, and this figure continues to grow. Our findings suggest that the production of the more viscous crude oils could be a large source of secondary organic aerosols in many production and refining regions worldwide, and that such production should be considered when assessing the environmental impacts of current and planned bitumen and heavy oil extraction projects globally.

The risk of melanoma with rasagiline compared with other antiparkinsonian medications: A retrospective cohort study in the United States medicare database.

PURPOSE: Compare the risk of melanoma between initiators of rasagiline or other antiparkinsonian drugs (APDs) in a Parkinson's disease (PD) population. METHODS: A retrospective cohort study was conducted in the US Medicare claims research database (2006-2015) in adults aged ≥65 years with PD claims. Other APD initiators were randomly matched (4:1) to rasagiline initiators on age, sex, and cohort entry year. Cutaneous melanoma events were identified by a validated claims algorithm. Incidence rates (IRs), incidence rate ratios (IRRs), and Cox-adjusted hazard ratios (HRs) for melanoma comparing rasagiline with other APD initiators were calculated and analyzed by duration of study medication use and cumulative dose of rasagiline. Potential indicators of surveillance bias were explored. RESULTS: Among 23 708 rasagiline initiators and 96 552 matched APD initiators, the crude IR of melanoma/100 000 person-years was 334.3 (95% confidence interval [CI], 291.5-381.6) and 208.2 (95% CI, 190.1-227.5), respectively (crude IRR 1.61; 95% CI, 1.36-1.89). The adjusted HR was 1.37 (95% CI, 1.14-1.65) and increased with longer rasagiline exposure and higher cumulative rasagiline doses. Rasagiline initiators more frequently had dermatologist visits or skin biopsies before cohort entry than APD initiators and had a higher incidence of nonmelanoma skin cancer during follow-up (crude IRR, 1.44; 95% CI, 1.35-1.54). CONCLUSIONS: A small increased incidence of melanoma with exposure to rasagiline compared with other APDs was observed. Although the pattern with dose and duration is consistent with a hypothesized biologic effect, the increased skin cancer surveillance among rasagiline users suggests surveillance bias as a contributing explanation for the observed results.

Intramolecular hydrogen bonding analysis.

The quasi-atomic orbital (QUAO) bonding analysis is used to study intramolecular hydrogen bonding (IMHB) in salicylic acid and an intermediate that is crucial to the synthesis of aspirin. The bonding analysis rigorously explores IMHB through directly accessing information that is intrinsic to the molecular wave function, thereby bypassing the need for intrinsically biased methods. The variables that affect the strength of IMHB are determined using kinetic bond orders, QUAO populations, and QUAO hybridizations. Important properties include both the interatomic distance between hydrogen and oxygen participating in the IMHB and the hybridization on the oxygen. The bonding analysis further shows that each intramolecular hydrogen bond is a four-electron three-center bond. The bonding analysis is used to understand how aromatic reactivity changes due to the effect of functional groups on the aromatic ring.