Direct observation of ultrafast hydrogen bond strengthening in liquid water.

Water is one of the most important, yet least understood, liquids in nature. Many anomalous properties of liquid water originate from its well-connected hydrogen bond network1, including unusually efficient vibrational energy redistribution and relaxation2. An accurate description of the ultrafast vibrational motion of water molecules is essential for understanding the nature of hydrogen bonds and many solution-phase chemical reactions. Most existing knowledge of vibrational relaxation in water is built upon ultrafast spectroscopy experiments2-7. However, these experiments cannot directly resolve the motion of the atomic positions and require difficult translation of spectral dynamics into hydrogen bond dynamics. Here, we measure the ultrafast structural response to the excitation of the OH stretching vibration in liquid water with femtosecond temporal and atomic spatial resolution using liquid ultrafast electron scattering. We observed a transient hydrogen bond contraction of roughly 0.04 Å on a timescale of 80 femtoseconds, followed by a thermalization on a timescale of approximately 1 picosecond. Molecular dynamics simulations reveal the need to treat the distribution of the shared proton in the hydrogen bond quantum mechanically to capture the structural dynamics on femtosecond timescales. Our experiment and simulations unveil the intermolecular character of the water vibration preceding the relaxation of the OH stretch.

Time-Resolved X-ray Emission Spectroscopy and Synthetic High-Spin Model Complexes Resolve Ambiguities in Excited-State Assignments of Transition-Metal Chromophores: A Case Study of Fe-Amido Complexes.

To fully harness the potential of abundant metal coordination complex photosensitizers, a detailed understanding of the molecular properties that dictate and control the electronic excited-state population dynamics initiated by light absorption is critical. In the absence of detectable luminescence, optical transient absorption (TA) spectroscopy is the most widely employed method for interpreting electron redistribution in such excited states, particularly for those with a charge-transfer character. The assignment of excited-state TA spectral features often relies on spectroelectrochemical measurements, where the transient absorption spectrum generated by a metal-to-ligand charge-transfer (MLCT) electronic excited state, for instance, can be approximated using steady-state spectra generated by electrochemical ligand reduction and metal oxidation and accounting for the loss of absorptions by the electronic ground state. However, the reliability of this approach can be clouded when multiple electronic configurations have similar optical signatures. Using a case study of Fe(II) complexes supported by benzannulated diarylamido ligands, we highlight an example of such an ambiguity and show how time-resolved X-ray emission spectroscopy (XES) measurements can reliably assign excited states from the perspective of the metal, particularly in conjunction with accurate synthetic models of ligand-field electronic excited states, leading to a reinterpretation of the long-lived excited state as a ligand-field metal-centered quintet state. A detailed analysis of the XES data on the long-lived excited state is presented, along with a discussion of the ultrafast dynamics following the photoexcitation of low-spin Fe(II)-Namido complexes using a high-spin ground-state analogue as a spectral model for the 5T2 excited state.

Characterization of Deformational Isomerization Potential and Interconversion Dynamics with Ultrafast X-ray Solution Scattering.

Dimeric complexes composed of d8 square planar metal centers and rigid bridging ligands provide model systems to understand the interplay between attractive dispersion forces and steric strain in order to assist the development of reliable methods to model metal dimer complexes more broadly. [Ir2 (dimen)4]2+ (dimen = para-diisocyanomenthane) presents a unique case study for such phenomena, as distortions of the optimal structure of a ligand with limited conformational flexibility counteract the attractive dispersive forces from the metal and ligand to yield a complex with two ground state deformational isomers. Here, we use ultrafast X-ray solution scattering (XSS) and optical transient absorption spectroscopy (OTAS) to reveal the nature of the equilibrium distribution and the exchange rate between the deformational isomers. The two ground state isomers have spectrally distinct electronic excitations that enable the selective excitation of one isomer or the other using a femtosecond duration pulse of visible light. We then track the dynamics of the nonequilibrium depletion of the electronic ground state population─often termed the ground state hole─with ultrafast XSS and OTAS, revealing a restoration of the ground state equilibrium in 2.3 ps. This combined experimental and theoretical study provides a critical test of various density functional approximations in the description of bridged d8-d8 metal complexes. The results show that density functional theory calculations can reproduce the primary experimental observations if dispersion interactions are added, and a hybrid functional, which includes exact exchange, is used.

Impact of race and ethnicity on outcomes after autologous stem cell transplantation for patients with newly diagnosed multiple myeloma.

Non-Hispanic Black patients are disproportionally affected by multiple myeloma (MM) and whether efficacy outcomes after autologous stem cell transplant (ASCT) differ by race and ethnicity remains an area of active investigation. This study included 449 patients enriched with a large proportion of non-Hispanic Black patients and sought to highlight the impact of race and ethnicity on outcomes after HDT-ASCT for patients with newly diagnosed MM. We found induction chemotherapy followed by high-dose therapy-ASCT and maintenance chemotherapy is associated with long-term PFS and OS, regardless of race or ethnicity.

Early versus standard management of chimeric antigen receptor therapy toxicities and management's impact on safety and efficacy.

BACKGROUND: Cytokine release syndrome (CRS) and immune effector cell-associated neurologic syndrome (ICANS) are well-documented toxicities of CAR T-cell therapy. To mitigate excessive toxicity, our center has formulated treatment protocols (early vs. standard) for timely management of CRS and ICANS with tocilizumab and/or corticosteroids. METHODS: This retrospective, single-center analysis included patients treated with CAR T-cell therapy. The goal was to describe the association of two management protocols with toxicity and efficacy outcomes. RESULTS: Fifty-five percent of the 40 patients assigned to early management, out of which 5% and 9% developed grade 3+ CRS and ICANS, respectively. Seventy-seven percent and 41% of these patients received tocilizumab and corticosteroids, respectively. Forty-five percent of patients were stratified as standard management, out of which 0% and 11% developed grade 3+ CRS and ICANS, respectively. Seventeen percent and 28% of these patients received tocilizumab and corticosteroids, respectively. The day +90 overall response rate (ORR) for all patients was 63%, with an ORR of 89% for those managed per early management versus 50% for those managed per standard protocol. CONCLUSION: Early use of tocilizumab and corticosteroids is effective in preventing excessive CAR-T-related toxicities with no negative impact on efficacy.

Impact of age, obesity, and renal impairment on outcomes after autologous stem cell transplantation for patients with newly diagnosed multiple myeloma.

INTRODUCTION: There remains a need to determine whether certain subgroups of newly diagnosed multiple myeloma (NDMM) derive the same benefit from high-dose chemotherapy-autologous stem cell transplant (HDT-ASCT). We describe our institutional experience highlighting the impact of age, obesity, and renal impairment on outcomes after HDT-ASCT for patients with NDMM in a real-world setting. METHODS: A total of 449 consecutive patients were included in this retrospective analysis. RESULTS: No difference in median progression free survival or overall survival was seen for patients with age > 65, body mass index (BMI) > 30 kg/m2, or estimated glomerular filtration rate < 60 mL/min/1.73 m2 when compared to those without these characteristics. From a safety standpoint, there were no differences in the incidence of transplant-related mortality or secondary malignancy among subgroups. CONCLUSION: For patients with NDMM undergoing HDT-ASCT, there is no difference in outcomes based on age, BMI, or renal function, and the presence of one or more of these factors should not preclude patients from HDT-ASCT.

Capturing Atom-Specific Electronic Structural Dynamics of Transition-Metal Complexes with Ultrafast Soft X-Ray Spectroscopy.

The atomic specificity of X-ray spectroscopies provides a distinct perspective on molecular electronic structure. For 3d metal coordination and organometallic complexes, the combination of metal- and ligand-specific X-ray spectroscopies directly interrogates metal-ligand covalency-the hybridization of metal and ligand electronic states. Resonant inelastic X-ray scattering (RIXS), the X-ray analog of resonance Raman scattering, provides access to all classes of valence excited states in transition-metal complexes, making it a particularly powerful means of characterizing the valence electronic structure of 3d metal complexes. Recent advances in X-ray free-electron laser sources have enabled RIXS to be extended to the ultrafast time domain. We review RIXS studies of two archetypical photochemical processes: charge-transfer excitation in ferricyanide and ligand photodissociation in iron pentacarbonyl. These studies demonstratefemtosecond-resolution RIXS can directly characterize the time-evolving electronic structure, including the evolution of the metal-ligand covalency.

Newly approved and forthcoming T-cell-redirecting bispecific antibodies for the treatment of relapsed/refractory multiple myeloma.

OBJECTIVE: Summarize the background, clinical trials, and place in therapy for the newly Food and Drug Administration (FDA) approved and forthcoming bispecific antibodies for relapsed/refractory (R/R) multiple myeloma. DATA SOURCES: A search of the PubMed database was conducted using the following search terms: B-cell maturation antigen (BCMA), teclistamab, myeloma, BsAbs, GPRC5D, and bispecific. Ongoing clinical trials as well as abstracts from ASH and ASCO evaluating the efficacy and safety of novel agents were evaluated. Prescribing information was also reviewed. SUMMARY: For patients with R/R multiple myeloma who have failed available therapies, treatment options are limited and survival is short. The FDA recently approved teclistamab, a T-cell-redirecting bispecific antibody, in patients with R/R multiple myeloma who have failed four prior lines of therapy. Teclistamab targets both CD3 expressed on T-cells and BCMA expressed on the surface of myeloma cells, mediating T-cell activation and lysis of plasma cells that express BCMA. Accelerated approval was granted based upon the results of the MajesTEC-1 study, which showed a durable response in a high proportion of heavily pretreated patients. Teclistamab is the first bispecific antibody approved for use in patients with multiple myeloma and the fourth approved agent targeting BCMA. Additional T-cell redirecting bispecific antibodies for use in multiple myeloma are also currently being studied. CONCLUSION: Teclistamab is the newest agent granted FDA approval for use in R/R multiple myeloma and represents a promising new option for patients. Ongoing trials are investigating teclistamab and other novel bispecific antibodies in the upfront and R/R setting.

Optically Induced Anisotropy in Time-Resolved Scattering: Imaging Molecular-Scale Structure and Dynamics in Disordered Media with Experiment and Theory.

Time-resolved scattering experiments enable imaging of materials at the molecular scale with femtosecond time resolution. However, in disordered media they provide access to just one radial dimension thus limiting the study of orientational structure and dynamics. Here we introduce a rigorous and practical theoretical framework for predicting and interpreting experiments combining optically induced anisotropy and time-resolved scattering. Using impulsive nuclear Raman and ultrafast x-ray scattering experiments of chloroform and simulations, we demonstrate that this framework can accurately predict and elucidate both the spatial and temporal features of these experiments.

Dissociation of Pyridinethiolate Ligands during Hydrogen Evolution Reactions of Ni-Based Catalysts: Evidence from X-ray Absorption Spectroscopy.

The protonation of several Ni-centered pyridine-2-thiolate photocatalysts for hydrogen evolution is investigated using X-ray absorption spectroscopy (XAS). While protonation of the pyridinethiolate ligand was previously thought to result in partial dechelation from the metal at the pyridyl N site, we instead observe complete dissociation of the protonated ligand and replacement by solvent molecules. A combination of Ni K-edge and S K-edge XAS of the catalyst Ni(bpy)(pyS)2 (bpy = 2,2'-bipyridine; pyS = pyridine-2-thiolate) identifies the structure of the fully protonated catalyst as a solvated [Ni(bpy)(DMF)4]2+ (DMF = dimethylformamide) complex and the dissociated ligands as the N-protonated 2-thiopyridone (pyS-H). This surprising result is further supported by UV-vis absorption spectroscopy and DFT calculations and is demonstrated for additional catalyst structures and solvent environments using a combination of XAS and UV-vis spectroscopy. Following protonation, electrochemical measurements indicate that the solvated Ni bipyridine complex acts as the primary electron-accepting species during photocatalysis, resulting in separate protonated ligand and reduced Ni species. The role of ligand dissociation is considered in the larger context of the hydrogen evolution reaction (HER) mechanism. As neither the pyS-H ligand nor the Ni bipyridine complex acts as an efficient HER catalyst alone, the critical role of ligand coordination is highlighted. This suggests that shifting the equilibrium toward bound species by addition of excess protonated ligand (2-thiopyridone) may improve the performance of pyridinethiolate-containing catalysts.

Quantifying the Steric Effect on Metal-Ligand Bonding in Fe Carbene Photosensitizers with Fe 2p3d Resonant Inelastic X-ray Scattering.

Understanding the electronic structure and chemical bonding of transition metal complexes is important for improving the function of molecular photosensitizers and catalysts. We have utilized X-ray absorption spectroscopy (XAS) and resonant inelastic X-ray scattering (RIXS) at the Fe L3 edge to investigate the electronic structure of two Fe N-heterocyclic carbene complexes with similar chemical structures but different steric effects and contrasting excited-state dynamics: [Fe(bmip)2]2+ and [Fe(btbip)2]2+, bmip = 2,6-bis(3-methyl-imidazole-1-ylidine)pyridine and btbip = 2,6-bis(3-tert-butyl-imidazole-1-ylidene)pyridine. In combination with charge transfer multiplet and ab initio calculations, we quantified how changes in Fe-carbene bond length due to steric effects modify the metal-ligand bonding, including σ/π donation and π back-donation. We find that σ donation is significantly stronger in [Fe(bmip)2]2+, whereas the π back-donation is similar in both complexes. The resulting stronger ligand field and nephelauxetic effect in [Fe(bmip)2]2+ lead to approximately 1 eV destabilization of the quintet metal-centered 5T2g excited state compared to [Fe(btbip)2]2+, providing an explanation for the absence of a photoinduced 5T2g population and a longer metal-to-ligand charge-transfer excited-state lifetime in [Fe(bmip)2]2+. This work demonstrates how combined modeling of XAS and RIXS spectra can be utilized to understand the electronic structure of transition metal complexes governed by correlated electrons and donation/back-donation interactions.

Safety and tolerability of lenalidomide maintenance dosing in patients with multiple myeloma post-autologous stem cell transplant.

BACKGROUND: For transplant-eligible newly diagnosed multiple myeloma patients, autologous hematopoietic stem cell transplant followed by maintenance lenalidomide is a standard of care practice. Maintenance lenalidomide dosing practices vary amongst physicians and current literature lacks comparisons on intermittent versus continuous dosing. In this retrospective study, we compared the safety, tolerability, and efficacy of continuous versus intermittent lenalidomide dosing. METHODS: This single-center, retrospective review included 72 patients with multiple myeloma receiving lenalidomide maintenance between 2018 and 2021. The primary objective was to determine the incidence of dose modification, defined as any dosage reduction, delay in treatment, or discontinuation of therapy. The secondary objectives were to determine the incidence of hematological and non-hematological toxicities between the two groups. RESULTS: A total of 58 patients in the continuous group and 14 patients in the intermittent group were included. Fifty-four percent of patients in the continuous group required dose modification versus 30% in the intermittent group. Patients who received continuous dosing appeared to have a higher incidence of adverse events when compared to intermittent dosing with the most common adverse events being neutropenia, fatigue, and rash. Twenty-four patients in the continuous group switched to an intermittent schedule after an adverse event. Of these patients, only 8% required further dose modification. CONCLUSION: The higher incidence of lenalidomide dose modifications in the continuous arm suggests that a majority of patients are not able to tolerate continuous lenalidomide maintenance. A more tolerable option for maintenance may be an intermittent schedule, as reflected by the favorable safety outcomes in this group.

Toxicity analysis of busulfan pharmacokinetic therapeutic dose monitoring.

Busulfan-based conditioning regimens are associated with serious toxicities and literature reports increased risk of toxicities when daily area under the curve concentrations exceed 6000 µM-minute. We implemented real time pharmacokinetic-guided therapeutic drug monitoring of busulfan for myeloablative conditioning regimens. The objective was to compare toxicity of intravenous busulfan before and after therapeutic drug monitoring implementation. The primary endpoint was incidence of hepatotoxicity. Medical records were retrospectively reviewed with weight-based dose Busulfan/Cyclophosphamide (BuCy) conditioning from August 2017 through March 2018 (N = 14) and therapeutic drug monitoring from April 2018 through December 2018 (N = 22). Recipients of busulfan therapeutic drug monitoring were younger than those receiving weight-based dose (median: 45 vs. 58 years, p = 0.008). No other baseline differences were observed. There was no difference in hepatotoxicity between therapeutic drug monitoring and weight-based dose (median 1 vs. 0 days, p = 0.40). In the therapeutic drug monitoring group, 45% of patients had increases and 41% had decreases in busulfan dose after Bu1. Repeat pharmacokinetic after Bu2 were required in 32% of patients. A pharmacokinetic dose monitoring program for myeloablative conditioning intravenous busulfan regimens may be considered a safe practice in stem cell transplant recipients. The majority of patients receiving pharmacokinetic-guided therapeutic drug monitoring required dose changes and therapeutic drug monitoring patients had no significant difference in toxicity compared to those receiving weight-based dose.

Reduction of Electron Repulsion in Highly Covalent Fe-Amido Complexes Counteracts the Impact of a Weak Ligand Field on Excited-State Ordering.

The ability to access panchromatic absorption and long-lived charge-transfer (CT) excited states is critical to the pursuit of abundant-metal molecular photosensitizers. Fe(II) complexes supported by benzannulated diarylamido ligands have been reported to broadly absorb visible light with nanosecond CT excited state lifetimes, but as amido donors exert a weak ligand field, this defies conventional photosensitizer design principles. Here, we report an aerobically stable Fe(II) complex of a phenanthridine/quinoline diarylamido ligand, Fe(ClL)2, with panchromatic absorption and a 3 ns excited-state lifetime. Using X-ray absorption spectroscopy (XAS) and resonant inelastic X-ray scattering (RIXS) at the Fe L-edge and N K-edge, we experimentally validate the strong Fe-Namido orbital mixing in Fe(ClL)2 responsible for the panchromatic absorption and demonstrate a previously unreported competition between ligand-field strength and metal-ligand (Fe-Namido) covalency that stabilizes the 3CT state over the lowest energy triplet metal-centered (3MC) state in the ground-state geometry. Single-crystal X-ray diffraction (XRD) and density functional theory (DFT) suggest that formation of this CT state depopulates an orbital with Fe-Namido antibonding character, causing metal-ligand bonds to contract and accentuating the geometric differences between CT and MC excited states. These effects diminish the driving force for electron transfer to metal-centered excited states and increase the intramolecular reorganization energy, critical properties for extending the lifetime of CT excited states. These findings highlight metal-ligand covalency as a novel design principle for elongating excited state lifetimes in abundant metal photosensitizers.

Publisher's Note: Femtosecond X-Ray Scattering Study of Ultrafast Photoinduced Structural Dynamics in Solvated [Co(terpy)_{2}]

This corrects the article DOI: 10.1103/PhysRevLett.117.013002.

Simulations of valence excited states in coordination complexes reached through hard X-ray scattering.

Hard X-ray spectroscopy selectively probes metal sites in complex environments. Resonant inelastic X-ray scattering (RIXS) makes it is possible to directly study metal-ligand interactions through local valence excitations. Here multiconfigurational wavefunction simulations are used to model valence K pre-edge RIXS for three metal-hexacyanide complexes by coupling the electric dipole-forbidden excitations with dipole-allowed valence-to-core emission. Comparisons between experimental and simulated spectra makes it possible to evaluate the simulation accuracy and establish a best-modeling practice. The calculations give correct descriptions of all LMCT excitations in the spectra, although energies and intensities are sensitive to the description of dynamical electron correlation. The consistent treatment of all complexes shows that simulations can rationalize spectral features. The dispersion in the manganese(iii) spectrum comes from unresolved multiple resonances rather than fluorescence, and the splitting is mainly caused by differences in spatial orientation between holes and electrons. The simulations predict spectral features that cannot be resolved in current experimental data sets and the potential for observing d-d excitations is also explored. The latter can be of relevance for non-centrosymmetric systems with more intense K pre-edges. These ab initio simulations can be used to both design and interpret high-resolution X-ray scattering experiments.

Tracking excited-state charge and spin dynamics in iron coordination complexes.

Crucial to many light-driven processes in transition metal complexes is the absorption and dissipation of energy by 3d electrons. But a detailed understanding of such non-equilibrium excited-state dynamics and their interplay with structural changes is challenging: a multitude of excited states and possible transitions result in phenomena too complex to unravel when faced with the indirect sensitivity of optical spectroscopy to spin dynamics and the flux limitations of ultrafast X-ray sources. Such a situation exists for archetypal polypyridyl iron complexes, such as [Fe(2,2'-bipyridine)3](2+), where the excited-state charge and spin dynamics involved in the transition from a low- to a high-spin state (spin crossover) have long been a source of interest and controversy. Here we demonstrate that femtosecond resolution X-ray fluorescence spectroscopy, with its sensitivity to spin state, can elucidate the spin crossover dynamics of [Fe(2,2'-bipyridine)3](2+) on photoinduced metal-to-ligand charge transfer excitation. We are able to track the charge and spin dynamics, and establish the critical role of intermediate spin states in the crossover mechanism. We anticipate that these capabilities will make our method a valuable tool for mapping in unprecedented detail the fundamental electronic excited-state dynamics that underpin many useful light-triggered molecular phenomena involving 3d transition metal complexes.

Excited state charge distribution and bond expansion of ferrous complexes observed with femtosecond valence-to-core x-ray emission spectroscopy.

Valence-to-core x-ray emission spectroscopy (VtC XES) combines the sample flexibility and element specificity of hard x-rays with the chemical environment sensitivity of valence spectroscopy. We extend this technique to study geometric and electronic structural changes induced by photoexcitation in the femtosecond time domain via laser-pump, x-ray probe experiments using an x-ray free electron laser. The results of time-resolved VtC XES on a series of ferrous complexes [Fe(CN)2n(2, 2'-bipyridine)3-n]-2n+2, n = 1, 2, 3, are presented. Comparisons of spectra obtained from ground state density functional theory calculations reveal signatures of excited state bond length and oxidation state changes. An oxidation state change associated with a metal-to-ligand charge transfer state with a lifetime of less than 100 fs is observed, as well as bond length changes associated with metal-centered excited states with lifetimes of 13 ps and 250 ps.

Hot Branching Dynamics in a Light-Harvesting Iron Carbene Complex Revealed by Ultrafast X-ray Emission Spectroscopy.

Iron N-heterocyclic carbene (NHC) complexes have received a great deal of attention recently because of their growing potential as light sensitizers or photocatalysts. We present a sub-ps X-ray spectroscopy study of an FeII NHC complex that identifies and quantifies the states involved in the deactivation cascade after light absorption. Excited molecules relax back to the ground state along two pathways: After population of a hot 3 MLCT state, from the initially excited 1 MLCT state, 30 % of the molecules undergo ultrafast (150 fs) relaxation to the 3 MC state, in competition with vibrational relaxation and cooling to the relaxed 3 MLCT state. The relaxed 3 MLCT state then decays much more slowly (7.6 ps) to the 3 MC state. The 3 MC state is rapidly (2.2 ps) deactivated to the ground state. The 5 MC state is not involved in the deactivation pathway. The ultrafast partial deactivation of the 3 MLCT state constitutes a loss channel from the point of view of photochemical efficiency and highlights the necessity to screen transition-metal complexes for similar ultrafast decays to optimize photochemical performance.