Arrhythmia Variant Associations and Reclassifications in the eMERGE-III Sequencing Study.

BACKGROUND: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results is unclear. In addition, the majority of discovered variants are currently classified as variants of uncertain significance, limiting clinical actionability. METHODS: The eMERGE-III study (Electronic Medical Records and Genomics Phase III) is a multicenter prospective cohort that included 21 846 participants without previous indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with electronic health record-derived phenotypes and follow-up clinical examination. Selected variants of uncertain significance (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells. RESULTS: As previously reported, 3.0% of participants had P/LP variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared with noncarriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their electronic health records. Fifty-four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long-QT syndrome), and 12 of these 19 diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance, we reclassified 11 variants: 3 to likely benign and 8 to P/LP. CONCLUSIONS: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As the genomes of large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, electronic health record phenotypes, and in vitro functional studies. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier; NCT03394859.

Education and electronic medical records and genomics network, challenges, and lessons learned from a large-scale clinical trial using polygenic risk scores.

Polygenic risk scores (PRS) have potential to improve health care by identifying individuals that have elevated risk for common complex conditions. Use of PRS in clinical practice, however, requires careful assessment of the needs and capabilities of patients, providers, and health care systems. The electronic Medical Records and Genomics (eMERGE) network is conducting a collaborative study which will return PRS to 25,000 pediatric and adult participants. All participants will receive a risk report, potentially classifying them as high risk (∼2-10% per condition) for 1 or more of 10 conditions based on PRS. The study population is enriched by participants from racial and ethnic minority populations, underserved populations, and populations who experience poorer medical outcomes. All 10 eMERGE clinical sites conducted focus groups, interviews, and/or surveys to understand educational needs among key stakeholders-participants, providers, and/or study staff. Together, these studies highlighted the need for tools that address the perceived benefit/value of PRS, types of education/support needed, accessibility, and PRS-related knowledge and understanding. Based on findings from these preliminary studies, the network harmonized training initiatives and formal/informal educational resources. This paper summarizes eMERGE's collective approach to assessing educational needs and developing educational approaches for primary stakeholders. It discusses challenges encountered and solutions provided.

Returning integrated genomic risk and clinical recommendations: The eMERGE study.

PURPOSE: Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk. METHODS: To enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores, monogenic risks, family history, and clinical risk assessments via a genome-informed risk assessment (GIRA) report and will assess uptake of care recommendations after return of results. RESULTS: GIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports. The return of high-risk GIRA to individuals and providers includes guidelines for care and lifestyle recommendations. Assembling the GIRA required infrastructure and workflows for ingesting and presenting content from multiple sources. Recruitment began in February 2022. CONCLUSION: Return of a novel report for communicating monogenic, polygenic, and family history-based risk factors will inform the benefits of integrated genetic risk assessment for routine health care.

Conducting inclusive research in genetics for transgender, gender-diverse, and sex-diverse individuals: Case analyses and recommendations from a clinical genomics study.

A person's phenotypic sex (i.e., endogenous expression of primary, secondary, and endocrinological sex characteristics) can impact crucial aspects of genetic assessment and resulting clinical care recommendations. In studies with genetics components, it is critical to collect phenotypic sex, information about current organ/tissue inventory and hormonal milieu, and gender identity. If researchers do not carefully construct data models, transgender, gender diverse, and sex diverse (TGSD) individuals may be given inappropriate care recommendations and/or be subjected to misgendering, inflicting medical and psychosocial harms. The recognized need for an inclusive care experience should not be limited to clinical practice but should extend to the research setting, where researchers must build an inclusive experience for TGSD participants. Here, we review three TGSD participants in the Family History and Cancer Risk Study (FOREST) to critically evaluate sex- and gender-related survey measures and associated data models in a study seeking to identify patients at risk for hereditary cancer syndromes. Furthermore, we leverage these participants' responses to sex- and gender identity-related questions in FOREST to inform needed changes to the FOREST data model and to make recommendations for TGSD-inclusive genetics research design, data models, and processes.

The reckoning: The return of genomic results to 1444 participants across the eMERGE3 Network.

PURPOSE: The goal of Electronic Medical Records and Genomics (eMERGE) Phase III Network was to return actionable sequence variants to 25,084 consenting participants from 10 different health care institutions across the United States. The purpose of this study was to evaluate system-based issues relating to the return of results (RoR) disclosure process for clinical grade research genomic tests to eMERGE3 participants. METHODS: RoR processes were developed and approved by each eMERGE institution's internal review board. Investigators at each eMERGE3 site were surveyed for RoR processes related to the participant's disclosure of pathogenic or likely pathogenic variants and engagement with genetic counseling. Standard statistical analysis was performed. RESULTS: Of the 25,084 eMERGE participants, 1444 had a pathogenic or likely pathogenic variant identified on the eMERGEseq panel of 67 genes and 14 single nucleotide variants. Of these, 1077 (74.6%) participants had results disclosed, with 562 (38.9%) participants provided with variant-specific genetic counseling. Site-specific processes that either offered or required genetic counseling in their RoR process had an effect on whether a participant ultimately engaged with genetic counseling (P = .0052). CONCLUSION: The real-life experience of the multiarm eMERGE3 RoR study for returning actionable genomic results to consented research participants showed the impact of consent, method of disclosure, and genetic counseling on RoR.

Metal-Organic Framework Magnets.

Metal-organic frameworks represent the ultimate chemical platform on which to develop a new generation of designer magnets. In contrast to the inorganic solids that have dominated permanent magnet technology for decades, metal-organic frameworks offer numerous advantages, most notably the nearly infinite chemical space through which to synthesize predesigned and tunable structures with controllable properties. Moreover, the presence of a rigid, crystalline structure based on organic linkers enables the potential for permanent porosity and postsynthetic chemical modification of the inorganic and organic components. Despite these attributes, the realization of metal-organic magnets with high ordering temperatures represents a formidable challenge, owing largely to the typically weak magnetic exchange coupling mediated through organic linkers. Nevertheless, recent years have seen a number of exciting advances involving frameworks based on a wide range of metal ions and organic linkers. This review provides a survey of structurally characterized metal-organic frameworks that have been shown to exhibit magnetic order. Section 1 outlines the need for new magnets and the potential role of metal-organic frameworks toward that end, and it briefly introduces the classes of magnets and the experimental methods used to characterize them. Section 2 describes early milestones and key advances in metal-organic magnet research that laid the foundation for structurally characterized metal-organic framework magnets. Sections 3 and 4 then outline the literature of metal-organic framework magnets based on diamagnetic and radical organic linkers, respectively. Finally, Section 5 concludes with some potential strategies for increasing the ordering temperatures of metal-organic framework magnets while maintaining structural integrity and additional function.

Associations between ethnicity and admission to intensive care among women giving birth: a cohort study.

OBJECTIVE: To determine the association between ethnic group and likelihood of admission to intensive care in pregnancy and the postnatal period. DESIGN: Cohort study. SETTING: Maternity and intensive care units in England and Wales. POPULATION OR SAMPLE: A total of 631 851 women who had a record of a registerable birth between 1 April 2015 and 31 March 2016 in a database used for national audit. METHODS: Logistic regression analyses of linked maternity and intensive care records, with multiple imputation to account for missing data. MAIN OUTCOME MEASURES: Admission to intensive care in pregnancy or postnatal period to 6 weeks after birth. RESULTS: In all, 2.24 per 1000 maternities were associated with intensive care admission. Black women were more than twice as likely as women from other ethnic groups to be admitted (odds ratio [OR] 2.21, 95% CI 1.82-2.68). This association was only partially explained by demographic, lifestyle, pregnancy and birth factors (adjusted OR 1.69, 95% CI 1.37-2.09). A higher proportion of intensive care admissions in Black women were for obstetric haemorrhage than in women from other ethnic groups. CONCLUSIONS: Black women have an increased risk of intensive care admission that cannot be explained by demographic, health, lifestyle, pregnancy and birth factors. Clinical and policy intervention should focus on the early identification and management of severe illness, particularly obstetric haemorrhage, in Black women, in order to reduce inequalities in intensive care admission. TWEETABLE ABSTRACT: Black women are almost twice as likely as White women to be admitted to intensive care during pregnancy and the postpartum period; this risk remains after accounting for demographic, health, lifestyle, pregnancy and birth factors.

Returning negative results from large-scale genomic screening: Experiences from the eMERGE III network.

Population-based genomic screening has the potential to improve health outcomes by identifying genetic causes of disease before they occur. While much attention has been paid to supporting the needs of the small percentage of patients who will receive a life-altering positive genomic screening result that requires medical attention, little attention has been given to the communication of negative screening results. As there are currently no best practices for returning negative genomic screening results, we drew on experiences across the electronic medical records and genomics (eMERGE) III Network to highlight the diversity of reporting methods employed, challenges encountered in reporting negative test results, and "lessons learned" across institutions. A 60-item survey that consisted of both multiple choice and open-ended questions was created to gather data across institutions. Even though institutions independently developed procedures for reporting negative results, and had very different study populations, we identified several similarities of approach, including but not limited to: returning results by mail, placing results in the electronic health record via an automated process, reporting results to participants' primary care provider, and providing genetic counseling to interested patients at no cost. Differences in procedures for reporting negative results included: differences in terminology used to describe negative results, definitions of negative results, guidance regarding the meaning of negative results for participants and their family members, and recommendations for clinical follow up. Our findings highlight emerging practices for reporting negative genomic screening results and highlight the need to create patient education and clinical support tools for reporting negative screening results.

Phenotyping coronavirus disease 2019 during a global health pandemic: Lessons learned from the characterization of an early cohort.

From the start of the coronavirus disease 2019 (COVID-19) pandemic, researchers have looked to electronic health record (EHR) data as a way to study possible risk factors and outcomes. To ensure the validity and accuracy of research using these data, investigators need to be confident that the phenotypes they construct are reliable and accurate, reflecting the healthcare settings from which they are ascertained. We developed a COVID-19 registry at a single academic medical center and used data from March 1 to June 5, 2020 to assess differences in population-level characteristics in pandemic and non-pandemic years respectively. Median EHR length, previously shown to impact phenotype performance in type 2 diabetes, was significantly shorter in the SARS-CoV-2 positive group relative to a 2019 influenza tested group (median 3.1 years vs 8.7; Wilcoxon rank sum P = 1.3e-52). Using three phenotyping methods of increasing complexity (billing codes alone and domain-specific algorithms provided by an EHR vendor and clinical experts), common medical comorbidities were abstracted from COVID-19 EHRs, defined by the presence of a positive laboratory test (positive predictive value 100%, recall 93%). After combining performance data across phenotyping methods, we observed significantly lower false negative rates for those records billed for a comprehensive care visit (p = 4e-11) and those with complete demographics data recorded (p = 7e-5). In an early COVID-19 cohort, we found that phenotyping performance of nine common comorbidities was influenced by median EHR length, consistent with previous studies, as well as by data density, which can be measured using portable metrics including CPT codes. Here we present those challenges and potential solutions to creating deeply phenotyped, acute COVID-19 cohorts.

Waterbirth: a national retrospective cohort study of factors associated with its use among women in England.

BACKGROUND: Waterbirth is widely available in English maternity settings for women who are not at increased risk of complications during labour. Immersion in water during labour is associated with a number of maternal benefits. However for birth in water the situation is less clear, with conclusive evidence on safety lacking and little known about the characteristics of women who give birth in water. This retrospective cohort study uses electronic data routinely collected in the course of maternity care in England in 2015-16 to describe the proportion of births recorded as having occurred in water, the characteristics of women who experienced waterbirth and the odds of key maternal and neonatal complications associated with giving birth in water. METHODS: Data were obtained from three population level electronic datasets linked together for the purposes of a national audit of maternity care. The study cohort included women who had no risk factors requiring them to give birth in an obstetric unit according to national guidelines. Multivariate logistic regression models were used to examine maternal (postpartum haemorrhage of 1500mls or more, obstetric anal sphincter injury (OASI)) and neonatal (Apgar score less than 7, neonatal unit admission) outcomes associated with waterbirth. RESULTS: 46,088 low and intermediate risk singleton term spontaneous vaginal births in 35 NHS Trusts in England were included in the analysis cohort. Of these 6264 (13.6%) were recorded as having occurred in water. Waterbirth was more likely in older women up to the age of 40 (adjusted odds ratio (adjOR) for age group 35-39 1.27, 95% confidence interval (1.15,1.41)) and less common in women under 25 (adjOR 18-24 0.76 (0.70, 0.82)), those of higher parity (parity ≥3 adjOR 0.56 (0.47,0.66)) or who were obese (BMI 30-34.9 adjOR 0.77 (0.70,0.85)). Waterbirth was also less likely in black (adjOR 0.42 (0.36, 0.51)) and Asian (adjOR 0.26 (0.23,0.30)) women and in those from areas of increased socioeconomic deprivation (most affluent versus least affluent areas adjOR 0.47 (0.43, 0.52)). There was no association between delivery in water and low Apgar score (adjOR 0.95 (0.66,1.36)) or incidence of OASI (adjOR 1.00 (0.86,1.16)). There was an association between waterbirth and reduced incidence of postpartum haemorrhage (adjOR 0.68 (0.51,0.90)) and neonatal unit admission (adjOR 0.65 (0.53,0.78)). CONCLUSIONS: In this large observational cohort study, there was no association between waterbirth and specific adverse outcomes for either the mother or the baby. There was evidence that white women from higher socioeconomic backgrounds were more likely to be recorded as giving birth in water. Maternity services should focus on ensuring equitable access to waterbirth.

Metal-Diamidobenzoquinone Frameworks via Post-Synthetic Linker Exchange.

Metal-organic frameworks with amidic linkers often exhibit exceptional physical properties, but, owing to their strong metal-nitrogen bonds, are exceedingly challenging to isolate through direct synthesis. Here, we report a route to access metal-diamidobenzoquinone frameworks from their dihydroxobenzoquinone counterparts via postsynthetic linker exchange. The parent compounds (Me2NH2)2[M2L3] (M = Zn, Mn; H2L = 2,5-dichloro-3,6-dihydroxo-1,4-benzoquinone) undergo linker exchange upon exposure to a solution of monodeprotonated 2,5-diamino-3,6-dibromo-1,4-benzoquinone or 2,5-diamino-3,6-dichloro-1,4-benzoquinone, proceeding through single-crystal-to-single-crystal reactions. The presence of both types of linker in the resulting frameworks is confirmed by a combination of NMR, Raman, and energy-dispersive X-ray (EDX) spectroscopies. Moreover, the extent of linker exchange in the Zn frameworks is quantified using 13C NMR spectroscopy, and spatially resolved EDX spectroscopy reveals the two types of linker to be homogeneously distributed within a crystal. Finally, we propose a tentative mechanism of linker exchange based on pKa measurements, considerations of framework solubility, and powder X-ray diffraction analysis. This work provides the first method to exchange organic linkers with different donor atoms in metal-organic frameworks and in doing so demonstrates exchange between linkers with donor atoms differing in acidity by a remarkable 11 units of pKa. Together, these results offer a potentially general synthetic strategy toward new materials with exotic metal-linker coordination modes.

Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

Ethical conflicts in translational genetic research: lessons learned from the eMERGE-III experience.

PURPOSE: The Electronic Medical Records and Genomics (eMERGE) Consortium integrated biorepository-based research with electronic health records (EHR) to return results from large-scale genetic tests to participants and uploaded those data into the EHR. This article explores the ethical issues investigators encountered in that process. METHODS: We conducted in-depth, semistructured interviews with study personnel of the eMERGE-III Consortium sites that returned results. RESULTS: We discuss major ethical issues that arose while attempting to return research results from the eMERGE Consortium to individual participants. These included difficulties recontacting those participants who had not explicitly consented to such and disclosing results to many participants with insufficient infrastructure and staff. Investigators reported being driven by a supererogatory clinical impulse. CONCLUSION: All these issues ultimately derive from ethical conflicts inherent to translational work being done at the interface of research and clinical care. A critical rethinking of this divide is important, but infrastructural support for such work is necessary for an ethically sound rollout of large-scale genetic testing.

Insensitivity of Magnetic Coupling to Ligand Substitution in a Series of Tetraoxolene Radical-Bridged Fe2 Complexes.

The elucidation of magnetostructural correlations between bridging ligand substitution and strength of magnetic coupling is essential to the development of high-temperature molecule-based magnetic materials. Toward this end, we report the series of tetraoxolene-bridged FeII2 complexes [(Me3TPyA)2Fe2(RL)]n+ (Me3TPyA = tris(6-methyl-2-pyridylmethyl)amine; n = 2: OMeLH2 = 3,6-dimethoxy-2,5-dihydroxo-1,4-benzoquinone, ClLH2 = 3,6-dichloro-2,5-dihydroxo-1,4-benzoquinone, Na2[NO2L] = sodium 3,6-dinitro-2,5-dihydroxo-1,4-benzoquinone; n = 4: SMe2L = 3,6-bis(dimethylsulfonium)-2,5-dihydroxo-1,4-benzoquinone diylide) and their one-electron-reduced analogues. Variable-temperature dc magnetic susceptibility data reveal the presence of weak ferromagnetic superexchange between FeII centers in the oxidized species, with exchange constants of J = +1.2(2) (R = OMe, Cl) and +0.3(1) (R = NO2, SMe2) cm-1. In contrast, X-ray diffraction, cyclic voltammetry, and Mössbauer spectroscopy establish a ligand-centered radical in the reduced complexes. Magnetic measurements for the radical-bridged species reveal the presence of strong antiferromagnetic metal-radical coupling, with J = -57(10), -60(7), -58(6), and -65(8) cm-1 for R = OMe, Cl, NO2, and SMe2, respectively. The minimal effects of substituents in the 3- and 6-positions of RLx-• on the magnetic coupling strength is understood through electronic structure calculations, which show negligible spin density on the substituents and associated C atoms of the ring. Finally, the radical-bridged complexes are single-molecule magnets, with relaxation barriers of Ueff = 50(1), 41(1), 38(1), and 33(1) cm-1 for R = OMe, Cl, NO2, and SMe2, respectively. Taken together, these results provide the first examination of how bridging ligand substitution influences magnetic coupling in semiquinoid-bridged compounds, and they establish design criteria for the synthesis of semiquinoid-based molecules and materials.

LPA Variants Are Associated With Residual Cardiovascular Risk in Patients Receiving Statins.

BACKGROUND: Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with statins decreases circulating levels of low-density lipoprotein cholesterol and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown. METHODS: We performed a 2-stage genome-wide association study of CHD events during statin therapy. We first identified 3099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7681 controls without CHD events during comparable intensity and duration of statin therapy from 4 sites in the Electronic Medical Records and Genomics Network. We then sought replication of candidate variants in another 160 cases and 1112 controls from a fifth Electronic Medical Records and Genomics site, which joined the network after the initial genome-wide association study. Finally, we performed a phenome-wide association study for other traits linked to the most significant locus. RESULTS: The meta-analysis identified 7 single nucleotide polymorphisms at a genome-wide level of significance within the LPA/PLG locus associated with CHD events on statin treatment. The most significant association was for an intronic single nucleotide polymorphism within LPA/PLG (rs10455872; minor allele frequency, 0.069; odds ratio, 1.58; 95% confidence interval, 1.35-1.86; P=2.6×10-10). In the replication cohort, rs10455872 was also associated with CHD events (odds ratio, 1.71; 95% confidence interval, 1.14-2.57; P=0.009). The association of this single nucleotide polymorphism with CHD events was independent of statin-induced change in low-density lipoprotein cholesterol (odds ratio, 1.62; 95% confidence interval, 1.17-2.24; P=0.004) and persisted in individuals with low-density lipoprotein cholesterol ≤70 mg/dL (odds ratio, 2.43; 95% confidence interval, 1.18-4.75; P=0.015). A phenome-wide association study supported the effect of this region on coronary heart disease and did not identify noncardiovascular phenotypes. CONCLUSIONS: Genetic variations at the LPA locus are associated with CHD events during statin therapy independently of the extent of low-density lipoprotein cholesterol lowering. This finding provides support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce CHD events in patients receiving statins.

Selective Binding and Quantitation of Calcium with a Cobalt-Based Magnetic Resonance Probe.

We report a cobalt-based paramagnetic chemical exchange saturation transfer (PARACEST) magnetic resonance (MR) probe that is able to selectively bind and quantitate the concentration of Ca2+ ions under physiological conditions. The parent LCo complex features CEST-active carboxamide groups and an uncoordinated crown ether moiety in close proximity to a high-spin pseudo-octahedral CoII center. Addition of Na+, Mg2+, K+, and Ca2+ leads to binding of these metal ions within the crown ether. Single-crystal X-ray diffraction and solid-state magnetic measurements reveal the presence of a cation-specific coordination environment and magnetic anisotropy of CoII, with axial zero-field splitting parameters for the Na+- and Ca2+-bound complexes differing by over 90%. Owing to these differences, solution-based measurements under physiological conditions indicate reversible binding of Na+ and Ca2+ to give well-separated CEST peaks at 69 and 80 ppm for [LCoNa]+ and [LCoCa]2+, respectively. Dissociation constants for different cation-bound complexes of LCo, as determined by 1H NMR spectroscopy, demonstrate high selectivity toward Ca2+. This finding, in conjunction with the large excess of Na+ in physiological environments, minimizes interference from related cations, such as Mg2+ and K+. Finally, variable-[Ca2+] CEST spectra establish the ratio between the CEST peak intensities for the Ca2+- and Na+-bound probes (CEST80 ppm/CEST69 ppm) as a measure of [Ca2+], providing the first example of a ratiometric quantitation of Ca2+ concentration using PARACEST. Taken together, these results demonstrate the ability of transition metal PARACEST probes to afford a concentration-independent measure of [Ca2+] and provide a new approach for designing MR probes for cation sensing.

Strong π-Backbonding Enables Record Magnetic Exchange Coupling Through Cyanide.

The paramagnetic cyano-bridged complex PhB(tBuIm)3Fe-NC-Mo(NtBuAr)3 (Ar = 3,5-Me2C6H3) is readily assembled from a new four-coordinate, high-spin (S = 2) iron(II) monocyanide complex and the three-coordinate molybdenum(III) complex Mo(NtBuAr)3. X-ray diffraction and IR spectroscopy reveal that delocalization of unpaired electron density into the cyanide π* orbitals leads to a reduction of the C-N bond order. Direct current (dc) magnetic susceptibility measurements, supported by electronic structure calculations, demonstrate the presence of strong antiferromagnetic exchange between spin centers, with a coupling constant of J = -122(2) cm-1. To our knowledge, this value represents the strongest magnetic exchange coupling ever to be observed through cyanide. These results demonstrate the ability of low-coordinate metal fragments to engender extremely strong magnetic exchange coupling through cyanide by virtue of significant π-backbonding into the cyanide ligand.

A Dimeric Hydride-Bridged Complex with Geometrically Distinct Iron Centers Giving Rise to an S = 3 Ground State.

Structural and spectroscopic characterization of the dimeric iron hydride complex [Ph2B(tBuIm)2FeH]2 reveals an unusual structure in which a tetrahedral iron(II) site (S = 2) is connected to a square planar iron(II) site (S = 1) by two bridging hydride ligands. Magnetic susceptibility reveals strong ferromagnetic coupling between iron centers, with a coupling constant of J = +110(12) cm-1, to give an S = 3 ground state. High-frequency and -field electron paramagnetic resonance (HFEPR) spectroscopy confirms this model. A qualitative molecular orbital analysis of the electronic structure, as supported by electronic structure calculations, reveals that the observed spin configuration results from the orthogonal alignment of two geometrically distinct four-coordinate iron fragments held together by highly covalent hydride ligands.

Thiosemiquinoid Radical-Bridged CrIII2 Complexes with Strong Magnetic Exchange Coupling.

Semiquinoid radical bridging ligands are capable of mediating exceptionally strong magnetic coupling between spin centers, a requirement for the design of high-temperature magnetic materials. We demonstrate the ability of sulfur donors to provide much stronger coupling relative to their oxygen congeners in a series of dinuclear complexes. Employing a series of chalcogen donor-based bis(bidentate) benzoquinoid bridging ligands, the series of complexes [(TPyA)2Cr2(RL4-)]2+ (OLH4 = 1,2,4,5-tetrahydroxybenzene, OSLH4 = 1,2-dithio-4,5-dihydroxybenzene, SLH4 = 1,2,4,5-tetrathiobenzene, TPyA = tris(2-pyridylmethyl)amine) was synthesized. Variable-temperature dc magnetic susceptibility data reveal the presence of weak antiferromagnetic superexchange coupling between CrIII centers in these complexes, with exchange constants of J = -2.83(3) (OL4-), -2.28(5) (OSL4-), and -1.80(2) (SL4-) cm-1. Guided by cyclic voltammetry and spectroelectrochemical measurements, chemical one-electron oxidation of these complexes gives the radical-bridged species [(TPyA)2Cr2(RL3-•)]3+. Variable-temperature dc susceptibility measurements in these complexes reveal the presence of strong antiferromagnetic metal-semiquinoid radical coupling, with exchange constants of J = -352(10) (OL3-•), - 401(8) (OSL3-•), and -487(8) (SL3-•) cm-1. These results provide the first measurement of magnetic coupling between metal ions and a thiosemiquinoid radical, and they demonstrate the value of moving from O to S donors in radical-bridged metal ions in the design of magnetic molecules and materials.

Protecting Privacy of Pregnant and LGBTQ+ Research Participants.

This Viewpoint summarizes existing federal regulations aimed at protecting research data, describes the challenges of enforcing these regulations, and discusses how evolving privacy technologies could be used to reduce health disparities and advance health equity among pregnant and LGBTQ+ research participants.