Using a Video Game Intervention to Increase Hospitalists' Advance Care Planning Conversations with Older Adults: a Stepped Wedge Randomized Clinical Trial.

BACKGROUND: Guidelines recommend Advance Care Planning (ACP) for seriously ill older adults to increase the patient-centeredness of end-of-life care. Few interventions target the inpatient setting. OBJECTIVE: To test the effect of a novel physician-directed intervention on ACP conversations in the inpatient setting. DESIGN: Stepped wedge cluster-randomized design with five 1-month steps (October 2020-February 2021), and 3-month extensions at each end. SETTING: A total of 35/125 hospitals staffed by a nationwide physician practice with an existing quality improvement initiative to increase ACP (enhanced usual care). PARTICIPANTS: Physicians employed for ≥ 6 months at these hospitals; patients aged ≥ 65 years they treated between July 2020-May 2021. INTERVENTION: Greater than or equal to 2 h of exposure to a theory-based video game designed to increase autonomous motivation for ACP; enhanced usual care. MAIN MEASURE: ACP billing (data abstractors blinded to intervention status). RESULTS: A total of 163/319 (52%) invited, eligible hospitalists consented to participate, 161 (98%) responded, and 132 (81%) completed all tasks. Physicians' mean age was 40 (SD 7); most were male (76%), Asian (52%), and reported playing the game for ≥ 2 h (81%). These physicians treated 44,235 eligible patients over the entire study period. Most patients (57%) were ≥ 75; 15% had COVID. ACP billing decreased between the pre- and post-intervention periods (26% v. 21%). After adjustment, the homogeneous effect of the game on ACP billing was non-significant (OR 0.96; 95% CI 0.88-1.06; p = 0.42). There was effect modification by step (p < 0.001), with the game associated with increased billing in steps 1-3 (OR 1.03 [step 1]; OR 1.15 [step 2]; OR 1.13 [step 3]) and decreased billing in steps 4-5 (OR 0.66 [step 4]; OR 0.95 [step 5]). CONCLUSIONS: When added to enhanced usual care, a novel video game intervention had no clear effect on ACP billing, but variation across steps of the trial raised concerns about confounding from secular trends (i.e., COVID). TRIAL REGISTRATION: Clinicaltrials.gov; NCT04557930, 9/21/2020.

Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID.

While immunologic correlates of COVID-19 have been widely reported, their associations with post-acute sequelae of COVID-19 (PASC) remain less clear. Due to the wide array of PASC presentations, understanding if specific disease features associate with discrete immune processes and therapeutic opportunities is important. Here we profile patients in the recovery phase of COVID-19 via proteomics screening and machine learning to find signatures of ongoing antiviral B cell development, immune-mediated fibrosis, and markers of cell death in PASC patients but not in controls with uncomplicated recovery. Plasma and immune cell profiling further allow the stratification of PASC into inflammatory and non-inflammatory types. Inflammatory PASC, identifiable through a refined set of 12 blood markers, displays evidence of ongoing neutrophil activity, B cell memory alterations, and building autoreactivity more than a year post COVID-19. Our work thus helps refine PASC categorization to aid in both therapeutic targeting and epidemiological investigation of PASC.

Immune checkpoint inhibitors in liver transplant: a case series.

Background: Immune checkpoint inhibitors (ICIs) in the setting of liver transplant (LT) pose a risk of rejection and hold unclear benefit in both the neoadjuvant (pre-transplant) and post-transplant salvage setting. In the pre-transplant setting, neoadjuvant ICIs may serve as a bridge to LT by downstaging disease burden to fit within transplant criteria. Outcomes in this setting include patients who had successful transplants without complications to patients who suffered severe complications, including fatal hepatic necrosis and graft failure requiring re-transplant. Some authors suggest having a period of three months between checkpoint inhibition and transplant may help mitigate adverse effects. In the post-LT setting, there are few treatment options if there is a recurrence of disease, which forces treatment teams to reconsider checkpoint inhibitors. Again, a longer period of time between transplant and checkpoint inhibition may reduce risk of rejection. Case reports of patients treated with ICIs post-transplant utilized either nivolumab or pembrolizumab. As combination atezolizumab/bevacizumab is a relatively new treatment option for unresectable hepatocellular carcinoma (HCC), there are only three reported cases using this combination in the post-LT setting. While there were no cases of rejection, all three cases had progression of disease. As immunotherapy joins transplantation as a mainstay of treatment for HCC, it remains unclear how to best navigate when the treatment course involves both immune activation and immunosuppression. Case Description: Patients who had an LT and were treated with ICIs (pre or post LT) at the University of Cincinnati were included in this retrospective chart review. Conclusions: Fatal rejection remains a significant risk even 4 years after LT. Neoadjuvant ICIs also pose a risk for acute cellular rejection; however, this may not always be clinically significant. Graft versus host disease (GVHD) may be an additional, previously unreported risk of ICIs in the setting of LT. Prospective studies are needed to understand benefits and risks of checkpoint inhibitors in the LT setting.

Dysregulated naive B cells and de novo autoreactivity in severe COVID-19.

Severe SARS-CoV-2 infection1 has been associated with highly inflammatory immune activation since the earliest days of the COVID-19 pandemic2-5. More recently, these responses have been associated with the emergence of self-reactive antibodies with pathologic potential6-10, although their origins and resolution have remained unclear11. Previously, we and others have identified extrafollicular B cell activation, a pathway associated with the formation of new autoreactive antibodies in chronic autoimmunity12,13, as a dominant feature of severe and critical COVID-19 (refs. 14-18). Here, using single-cell B cell repertoire analysis of patients with mild and severe disease, we identify the expansion of a naive-derived, low-mutation IgG1 population of antibody-secreting cells (ASCs) reflecting features of low selective pressure. These features correlate with progressive, broad, clinically relevant autoreactivity, particularly directed against nuclear antigens and carbamylated proteins, emerging 10-15 days after the onset of symptoms. Detailed analysis of the low-selection compartment shows a high frequency of clonotypes specific for both SARS-CoV-2 and autoantigens, including pathogenic autoantibodies against the glomerular basement membrane. We further identify the contraction of this pathway on recovery, re-establishment of tolerance standards and concomitant loss of acute-derived ASCs irrespective of antigen specificity. However, serological autoreactivity persists in a subset of patients with postacute sequelae, raising important questions as to the contribution of emerging autoreactivity to continuing symptomology on recovery. In summary, this study demonstrates the origins, breadth and resolution of autoreactivity in severe COVID-19, with implications for early intervention and the treatment of patients with post-COVID sequelae.

Videogame intervention to increase advance care planning conversations by hospitalists with older adults: study protocol for a stepped-wedge clinical trial.

INTRODUCTION: Fewer than half of all people in the USA have a documented advance care plan (ACP). Hospitalisation offers an opportunity for physicians to initiate ACP conversations. Despite expert recommendations, hospital-based physicians (hospitalists) do not routinely engage in these conversations, reserving them for the critically ill.The objective of this study is to test the effect of a novel behavioural intervention on the incidence of ACP conversations by hospitalists practicing at a stratified random sample of hospitals drawn from 220 US acute care hospitals staffed by a large, nationwide acute care physician practice with an ongoing ACP quality improvement initiative. METHODS AND ANALYSIS: We developed Hopewell Hospitalist, a theory-based adventure video game, to modify physicians' attitudes towards ACP conversations and to increase their motivation for engaging in them. The planned study is a pragmatic stepped-wedge crossover phase III trial, testing the efficacy of Hopewell Hospitalist for increasing ACP conversations. We will randomise 40 hospitals to the month (step) in which they receive the intervention. We aim to recruit 30 hospitalists from up to eight hospitals each step to complete the intervention, playing Hopewell Hospitalist for at least 2 hours. The primary outcome is ACP billing for patients aged 65 and older managed by participating hospitalists. We hypothesise that the intervention will increase ACP billing in the quarter after dissemination, and have 80% power to detect a 1% absolute increase and 99% power to detect a 3.5% absolute increase. ETHICS AND DISSEMINATION: Dartmouth's Committee for the Protection of Human Subjects has approved the study protocol, which is registered on clinicaltrials.gov. We will disseminate the results through manuscripts and the trials website. Hopewell Hospitalist will be made available on the iOS Application Store for download, free of cost, at the conclusion of the trial. TRIAL REGISTRATION NUMBER: NCT04557930.

Capillary Blood Levels of Hydroxychloroquine and Methotrexate Are Stable for up to 5 Years When Collected on Volumetric Absorptive Microsamplers.

BACKGROUND: Hydroxychloroquine (HCQ) and methotrexate (MTX) are common antirheumatic drugs used chronically by patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) (1, 2). Therapeutic drug monitoring (TDM) of HCQ and MTX provides critical compliance information, but typically requires venipuncture and shipment of refrigerated blood samples to the clinical laboratory. Capillary blood collection by finger prick offers a convenient alternative to venipuncture. The long-term stability of capillary blood HCQ and MTX collected using volumetric absorptive microsamplers (VAMS) has not previously been evaluated. In this study, we evaluated the stability of capillary MTX and HCQ levels when stored on VAMS for up to 5 years. METHODS: Samples of patients with RA and SLE were collected for HCQ or MTX monitoring as part of 2 clinical studies in 2015 (HCQ: n = 24 | MTX: n = 61) and 2017 (HCQ: n = 126). Venous and capillary blood samples were shipped to Exagen Inc.'s clinical laboratory. HCQ and MTXPG3 were measured using separate LC-MS/MS methodologies. Baseline venous blood levels of HCQ and MTXPG3 were determined within 1 week of draw and compared to capillary blood levels determined following 3 or 5 years of storage. RESULTS: Venous blood HCQ and capillary blood MTXPG3 determinations made at baseline were significantly different from capillary blood determinations performed following 5 years of storage at -80 °C. However, these differences were within the specified limits of agreement [HCQ: Avg % change after storage (CI 95%) = -7.1% (-12.6, -1.6%), pt-test = 0.0205, interclass correlation coefficient (ICC) = 0.96 | MTXPG3: Avg % change after storage (CI 95%) = 13.3% (7.1, 19.4%), pt-test = 0.0001, ICC = 0.90]. CONCLUSION: Dried capillary blood HCQ and MTXPG3 levels collected on VAMS are stable for up to 5 years.

A New Standard for Advance Care Planning (ACP) Conversations in the Hospital: Results from a Delphi Panel.

BACKGROUND: Fewer than half of the US population has an advance healthcare directive. Hospitalizations offer a key opportunity for clinicians to engage patients in advance care planning (ACP) conversations. Guidelines suggest screening for the presence of "serious illness" but do not further specify how to prioritize the 12.4 million patients hospitalized each year. OBJECTIVE: To establish a normative standard for prioritizing hospitalized patients for ACP conversations. DESIGN AND SETTING: A modified Delphi study, with three iterative rounds of online surveys. PARTICIPANTS: Multi-disciplinary group of US-based clinicians with research and practical expertise in ACP. MAIN MEASURES: Indirect and direct elicitation of short-term and 1-year risk of mortality that prompt experts to prioritize ACP conversations for hospitalized adults. MAIN RESULTS: Fifty-seven of 108 (52%) candidate panelists completed round 1, and 47 completed rounds 2 and 3. Panelists were primarily physicians (84%), with significant experience (mean years 23 [SD 9.8]), who either taught (55%) and/or performed research about ACP (55%). In round 1, > 70% of panelists agreed that all hospitalized adults ≥ 65 years should have an ACP conversation before discharge, but disagreed about the timing and content of the conversation. By round 3, > 70% of participants agreed that patients with either high (> 10%) short-term or high (≥ 34%) 1-year risk of mortality should have a goals of care conversation (i.e., focused on preferences for near-term treatment), while patients with low (≤ 10%) short-term and low (< 19%) 1-year risk of mortality warranted an ACP conversation (i.e., focused on preferences for future care) before discharge. LIMITATIONS: Use of case vignettes to elicit clinician judgment; response rate. CONCLUSIONS: Panelists agreed that clinicians should have an ACP conversation with all hospitalized adults over 65 years in an ACP conversation, adjusting the content and timing of the conversation conditional on the patient's risk of short-term and 1-year mortality.

Relaxed peripheral tolerance drives broad de novo autoreactivity in severe COVID-19.

An emerging feature of COVID-19 is the identification of autoreactivity in patients with severe disease that may contribute to disease pathology, however the origin and resolution of these responses remain unclear. Previously, we identified strong extrafollicular B cell activation as a shared immune response feature between both severe COVID-19 and patients with advanced rheumatic disease. In autoimmune settings, this pathway is associated with relaxed peripheral tolerance in the antibody secreting cell compartment and the generation of de novo autoreactive responses. Investigating these responses in COVID-19, we performed single-cell repertoire analysis on 7 patients with severe disease. In these patients, we identify the expansion of a low-mutation IgG1 fraction of the antibody secreting cell compartment that are not memory derived, display low levels of selective pressure, and are enriched for autoreactivity-prone IGHV4-34 expression. Within this compartment, we identify B cell lineages that display specificity to both SARS-CoV-2 and autoantigens, including pathogenic autoantibodies against glomerular basement membrane, and describe progressive, broad, clinically relevant autoreactivity within these patients correlated with disease severity. Importantly, we identify anti-carbamylated protein responses as a common hallmark and candidate biomarker of broken peripheral tolerance in severe COVID-19. Finally, we identify the contraction of this pathway upon recovery, and re-establishment of tolerance standards coupled with a concomitant loss of acute-derived ASCs irrespective of antigen specificity. In total, this study reveals the origins, breadth, and resolution of acute-phase autoreactivity in severe COVID-19, with significant implications in both early interventions and potential treatment of patients with post-COVID sequelae.

Perspectives on Patient Experience: A National Survey of Hospitalists.

Despite efforts to improve patient experience (PX), little is known about the perspective of hospitalists regarding PX initiatives and priorities. A survey was distributed to hospitalist groups across the country assessing involvement in PX initiatives and their perceived effectiveness, what PX means to providers, and facilitators/barriers in improving PX. Ninety-nine percent of respondents had encountered some improvement activity around PX. The most prevalent were communication training, group Hospital Consumer Assessment of Healthcare Providers and Systems data, and interdisciplinary bedside rounding. Respondents rated most initiatives a 5 to 6 out of 10 for their effectiveness, with the perception of effectiveness increasing with respondents' assessment of patient experience priority. Learning about others' experiences in improving PX and learning about potential collaborations for quality improvement or research in these areas were areas of interest for future work. Qualitative work highlighted potential barriers in improving PX such as workload and staffing constraints, uncontrollable environmental factors, and unrealistic patient expectations. Improving PX is a priority, and there are many initiatives in place with perceived variable success and perceived barriers in improving PX.

Characteristics of regulatory T-cell populations before and after Ty21a typhoid vaccination in children and adults.

Typhoid fever, caused by the pathogen Salmonella enterica serovar Typhi (S. Typhi), is a serious global health concern. Challenge studies with wild type S. Typhi identified associations between gut-homing regulatory T cells (Treg) and development of typhoid disease. Whether oral live-attenuated Ty21a vaccination induces gut-homing Treg remains unclear. Here, we analyze pediatric and adult Treg pre- and post-Ty21a vaccination in an autologous S. Typhi-antigen presentation model to address this knowledge gap. We show that peripheral memory Treg populations change from childhood to adulthood, but not following Ty21a vaccination. Unsupervised dimensionality reduction with t-distributed stochastic neighbor embedding (tSNE) identifies homing, memory, and functional features which evidence age-associated maturation of multifunctional S. Typhi-responsive Treg, which were not impacted by Ty21a vaccination. These findings improve understanding of pediatric regulatory T cells, while identifying age-related differences in S. Typhi-responsive Treg, which may aid in the development of improved pediatric vaccination strategies against S. Typhi.

Diversity of Salmonella Typhi-responsive CD4 and CD8 T cells before and after Ty21a typhoid vaccination in children and adults.

Typhoid fever is a life-threatening disease caused by the human-restricted pathogen Salmonella enterica serovar Typhi (S. Typhi). The oral live attenuated Ty21a typhoid vaccine protects against this severe disease by eliciting robust, multifunctional cell-mediated immunity (CMI), shown to be associated with protection in wild-type S. Typhi challenge studies. Ty21a induces S. Typhi-responsive CD8+ and CD4+ T cells but little is known about the response to this vaccine in children. To address this important gap in knowledge, we have used mass cytometry to analyze pediatric and adult pre- and post-Ty21a vaccination CMI in an autologous S. Typhi antigen presentation model. Here, using conventional supervised analytical tools, we show adult T cells are more multifunctional at baseline than those obtained from children. Moreover, pediatric and adult T cells respond similarly to Ty21a vaccination, but adult responders remain more multifunctional. The use of the unsupervised dimensionality reduction tool tSNE (t-distributed Stochastic Neighbor Embedding) allowed us to confirm these findings, as well as to identify increases and decreases in well-defined specific CD4+ and CD8+ T-cell populations that were not possible to uncover using the conventional gating strategies. These findings evidenced age-associated maturation of multifunctional S. Typhi-responsive T-cell populations, including those which we have previously shown to be associated with protection from, and/or delayed onset of, typhoid disease. These findings are likely to play an important role in improving pediatric vaccination strategies against S. Typhi and other enteric pathogens.

Age-Associated Heterogeneity of Ty21a-Induced T Cell Responses to HLA-E Restricted Salmonella Typhi Antigen Presentation.

Human-restricted Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever-a life-threatening disease of great global health significance, particularly in the developing world. Ty21a is an oral live-attenuated vaccine that protects against the development of typhoid disease in part by inducing robust T cell responses, among which multifunctional CD8+ cytotoxic T lymphocytes (CTL) play an important role. Following Ty21a vaccination, a significant component of adult CTL have shown to be targeted to S. Typhi antigen presented by the conserved major histocompatibility complex (MHC) class Ib molecule, human leukocyte antigen-E (HLA-E). S. Typhi challenge studies have shown that baseline, multifunctional HLA-E responsive T cells are associated with protection from, and delayed onset of, typhoid disease. However, despite the overwhelming burden of typhoid fever in school-aged children, and due to limited availability of pediatric samples, incomplete information is available regarding these important HLA-E-restricted responses in children, even though studies have shown that younger children may be less likely to develop protective cell mediated immune (CMI) responses than adults following vaccination. To address this gap, we have studied this phenomenon in depth by using mass cytometry to analyze pediatric and adult T cell responses to HLA-E-restricted S. Typhi antigen presentation, before and after Ty21a vaccination. Herein, we show variable responses in all age strata following vaccination among T effector memory (TEM) and T effector memory CD45RA+ (TEMRA) cells based on conventional gating analysis. However, by utilizing the dimensionality reduction tool tSNE (t-distributed Stochastic Neighbor Embedding), we are able to identify diverse, highly multifunctional gut-homing- TEM and TEMRA clusters of cells which are more abundant in adult and older pediatric participants than in younger children. These findings highlight a potential age-associated maturation of otherwise conserved HLA-E restricted T cell responses. Such insights, coupled with the marked importance of multifunctional T cell responses to combat infection, may better inform future pediatric vaccination strategies against S. Typhi and other infectious diseases.

Differences Between Pediatric and Adult T Cell Responses to In Vitro Staphylococcal Enterotoxin B Stimulation.

Toxic shock syndrome (TSS) is capable of inducing life-threatening fever, rash, and systemic organ failure, though the specific mechanisms behind these symptoms remain poorly understood. Staphylococcal enterotoxin B (SEB) and other superantigens have shown to be important factors in TSS, capable of promoting cross-linking between T cell receptors and major histocompatibility complexes which results in overwhelming T cell activation, proliferation, and cytokine production. The resulting proinflammatory cytokine cascade, often referred to as the "cytokine storm," seems to be critical to the development of disease. Interestingly, clinical studies have shown that children exhibit less severe TSS-associated morbidity than adults, though the mechanism behind this phenomenon has not been addressed. Indeed, despite the fact that most novel antigen exposure occurs early in life, be it from environmentally acquired pathogens or routine vaccination, normal pediatric T cell immune functions remain critically underexplored. This is largely due to difficulty in obtaining enough samples to explore more than a narrow sliver of the cell-mediated immune compartment. To address this limitation, we optimized a T effector (Teff)/circulating T follicular helper (cTFH) cell mass cytometry panel which allowed us to analyze a wide array of T cell populations and effector functions following in vitro SEB stimulation. We show that T cell activation-as measured by CD69 expression-following SEB stimulation is lower in pediatric participants, increasing throughout childhood, and reaching adult levels by around 15 years old. Further, while individual CD4+ effector memory T cell (TEM) effector molecules show limited age-associated differences following SEB stimulation, multifunctional CD4+ TEM are shown to positively correlate with increasing age through adolescence. Individual CD8+ TEM effectors and multifunctional phenotypes also show very strong age-associated increases following SEB stimulation. SEB stimulation has little impact on cTFH activation or functional cellular markers, regardless of age. These results, coupled with the fact that a robust proinflammatory cytokine response seems critical to developing severe TSS, suggest a possible connection between the significantly reduced T cell activation and multifunctional populations following in vitro SEB stimulation in our pediatric participants and clinical observations relating to reduced TSS mortality in children.

Performance of conventional and range-separated hybrid density functionals in calculations of electronic circular dichroism spectra of transition metal complexes.

A number of density functionals, including 'pure' (nonhybrid) functionals, global hybrids, and range-separated hybrids, were used to calculate the electronic circular dichroism (CD) spectra of 10 tris-bidentate transition metal complexes. The results are compared to one another and to experimental CD spectra, in an effort to illustrate the shortcomings of particular approximations in time-dependent density functional theory (TDDFT). The use of an origin invariant formalism to calculate magnetic transition dipole moments with the help of gauge-including atomic orbitals (GIAOs) is also investigated. With valence basis sets of moderate flexibility, good agreement between GIAO results and rotatory strengths calculated from the dipole-velocity representation is obtained for selected test cases. Empirically broadened vertical CD spectra calculated with the global hybrid functionals B3LYP and PBE0 are found to agree overall the best with experimental CD spectra.

Multifunctional and reactive enantiopure organometallic helicenes: tuning chiroptical properties by structural variations of mono- and bis(platinahelicene)s.

Acetylacetonato-platina[6]- and -platina[7]helicenes have been prepared from 2-pyridyl-substituted benzophenanthrene ligands by following a two-step cycloplatination reaction. The photophysical properties (UV-visible absorption and emission behavior) and chiroptical properties (circular dichroism and molar rotation) of the resolved enantiomers have been measured. These metallahelicenes constitute a novel family of easily accessible helicene derivatives that exhibit large and tuneable chiroptical properties that can be rationalized theoretically and compared to the parent [6]- and [7]carbohelicenes. Furthermore, they are red phosphors at room temperature and their large chiroptical properties can be modulated by oxidation of the metal center to Pt(IV). Hetero- and homochiral diastereomeric bis(metallahelicene)s that possess a rare Pt(III)-Pt(III) scaffold bridged by benzoato ligands have also been prepared. It is shown that the heterochiral (P,M)-bis(Pt(III)-[6]helicene) 9a(1) can isomerize into the homochiral (P,P)- and (M,M)-bis(Pt(III)-[6]helicene) 9a(2). Spectral assignments and an analysis of the optical rotation of these systems were made with the help of time-dependent density functional theory. The calculations highlight the contributions of the metal centers to the chiroptical properties. For 9a(1) and 9a(2), σ-π conjugation between the helicenes and the Pt-Pt moiety may contribute strongly to the optical rotation and electronic circular dichroism.

Calculation of optical rotatory dispersion and electronic circular dichroism for tris-bidentate groups 8 and 9 metal complexes, with emphasis on exciton coupling.

The optical rotatory dispersion (ORD, both non-resonant and resonant) and the electronic circular dichroism (CD) of tris-bidentate transition metal complexes of the form [M(L)(3)](n+) (M = Fe, Ru, Os, Co, Rh, Ir; n = 2, 3; L = 1,10-phenanthroline, 2,2'-bipyridine) are calculated using time-dependent density functional theory (TDDFT). The exciton CD band resulting from the coupling of ligand π-to-π* transitions is investigated in detail and analyzed in terms of exciton coupling of long-axis transitions using a dipole coupling model that takes TDDFT data for a single ligand as input. Results of the coupling model agree well with the full TDDFT CD spectra. The usefulness and reliability of this model is discussed. The resonant ORDs calculated directly from analytical damped linear TDDFT response compare well with Kramers-Kronig transformations of the calculated CD spectra. For comparisons of resonant ORD with experiment, one needs to consider wavelength shifts.

Time-dependent density functional response theory for electronic chiroptical properties of chiral molecules.

Methodology to calculate electronic chiroptical properties from time-dependent density functional theory (TDDFT) is outlined. Applications of TDDFT to computations of electronic circular dichroism, optical rotation, and optical rotatory dispersion are reviewed. Emphasis is put on publications from 2005 to 2010, but much of the older literature is also cited and discussed. The determination of the absolute configuration of chiral molecules by combined measurements and computations is an important application of TDDFT chiroptical methods and discussed in some detail. Raman optical activity (ROA) spectra are obtained from normal-mode derivatives of the optical rotation tensor and other linear response tensors. A few selected (ROA) benchmarks are reviewed.

From hetero- to homochiral bis(metallahelicene)s based on a Pt(III)-Pt(III) bonded scaffold: isomerization, structure, and chiroptical properties.

Hetero- and homochiral diastereomeric bis(metallahelicene)s have been synthesized. They possess a rare Pt(III)-Pt(III) scaffold bridged by benzoato ligands. It is shown that heterochiral (P,M)-bis(Pt(III)-[6]helicene) can isomerize into the homochiral (P,P)- and (M,M)-bis(Pt(III)-[6]helicene). A theoretical study shows a unique σ-π conjugation between the two π-helices and the σ-Pt(III)-Pt(III) scaffold that impacts the strong chiroptical properties.

Assembly of pi-conjugated phosphole azahelicene derivatives into chiral coordination complexes: an experimental and theoretical study.

Aza[n]helicene phosphole derivatives have been prepared from aza[n]helicene diynes by the Fagan-Nugent route. Their photophysical properties (UV/Vis absorption and emission behavior) have been evaluated. Their behavior as P,N chelates towards coordination to Pd(II) and Cu(I) has been investigated: metal-bis(aza[n]helicene phosphole) assemblies are formed by a highly stereoselective coordination process, as demonstrated by X-ray crystallography. An aza[6]helicene phosphole bearing an enantiopure helicene part has been obtained, which allows the preparation of enantiopure Pd(II) and Cu(I) complexes with original topologies and high molar rotation (MR) and circular dichroism (CD). The structure-property relationship established from the experimental data has been studied in detail by theoretical studies (TDDFT calculations of UV/Vis, CD, and MR). Aza[n]helicene phosphole derivatives show pi conjugation extended over the entire molecule, and its influence on the MR of aza[6]helicene phosphole 5 c has been demonstrated. Finally, it has been shown that the nature of the metal (coordination geometry and electronic interaction) can have a great impact on the amplitude of the chiroptical properties in metal-bis(aza[n]helicene phosphole) assemblies.