A comparison of clinical, utilization, and cost outcomes between oral treatments for multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) affects nearly 1 million people in the United States and causes significant disability and economic loss. Among the first available oral MS treatment options, clinical outcome comparisons and associated health care resource utilization are not clearly defined. OBJECTIVE: To compare MS outcomes, health care resource utilization, and relative costs across treatment with dimethyl fumarate (DMF), fingolimod (FG), or teriflunomide (TERI) among Medicare Advantage Prescription Drug (MAPD) plan and commercially insured beneficiaries. METHODS: This retrospective cohort study used the Humana Research Database. Eligible study patients had their first MS medication claim for oral DMG, FG, or TERI between January 1, 2013, and December 31, 2018. Patients were followed for a minimum of 12 months (mean follow-up = 3.8 years), until the earliest of the following occurred: health plan disenrollment, the end of the study period, or death. Study cohorts were balanced with inverse probability of treatment weighting. All-cause and MS-related health care resource utilization, time on therapy, and time after therapy were compared using inverse probability of treatment-adjusted multivariate generalized linear models across treatment groups. Relative costs were compared using a generalized linear model with a gamma distribution and log link. RESULTS: We identified 1,442 patients in 3 medication groups: DMF (n = 843), FG (n = 213), and TERI (n = 386). After weighting, there were no significant differences between the medication groups on demographic and clinical characteristics. Time on therapy (days) was significantly different across medication groups (P < 0.001). Time on therapy was longest for FG compared with the DM and TERI groups (644 vs 462 vs 521). The number discontinuing the index medication was significantly different for FG vs DMF vs TERI (74.7% vs 85.3% vs 80.7%; P < 0.001). FG had the lowest discontinuation rate. The mean (SD) annualized relapse rates (ARRs) were 0.47 (0.80), 0.42 (1.3), and 0.53 (1.3) (P = 0.037) for DMF, FG, and TERI, respectively. The percentage of those experiencing inpatient stays and the number of stays (mean [SD]) were significantly different among the FG group vs DMF vs TERI (29.9% vs 34.1% vs 40.9%; P < 0.001) and (0.57 [2.9] vs 0.74 [1.9] vs 0.91 [3.5]; P = 0.007), respectively. All-cause emergency department visits and the number of visits (mean [SD]) were significantly different for the FG cohort vs DMF vs TERI (46% vs 54.3% vs 61%; P < 0.001) and (1.84 [7.7] vs 2.38 [5.9] vs 2.87 [8.8]; P = 0.002), respectively. FG had the lowest impatient stays and emergency department visits of the 3 groups. CONCLUSIONS: Patients with MS initiated on FG used fewer health care resources and experienced lower ARR compared with patients on DMF and TERI.

HIV preexposure prophylaxis treatment patterns in a national health plan population.

BACKGROUND: Medication nonadherence diminishes the benefits of preexposure prophylaxis (PrEP) for the 1.2 million Americans at risk for HIV exposure. OBJECTIVE: To describe HIV PrEP treatment patterns among Medicare Advantage Prescription Drug (MAPD) plan and commercially insured beneficiaries. METHODS: This retrospective cohort study identified patients aged 16 to 89 years with at least 1 dispensing of emtricitabine-tenofovir disoproxil fumarate from July 2012, through December 2020, or emtricitabine-tenofovir alafenamide from October 2019 through December 2020, and who were continuously enrolled at least 12 months prior to and following the earliest PrEP claim. Outcomes were HIV PrEP adherence measured by proportion of days covered (PDC) using 2 binary thresholds of 0.60 (4 doses/week) and 0.80 (5-6 doses/week) and duration of index treatment episode, total time on treatment, and total number of prescription fills. RESULTS: The study cohort of 707 (292 MAPD plan, 415 commercial) was predominantly made up of male patients (90.0%) and resided in the South (78.9%) with a mean age of 46.2 years (MAPD plan: 54.5, commercial: 40.4). Both populations engaged in high-risk sexual behavior (All: 18.7%, MAPD plan: 16.8%, commercial: 20.0%) and experienced sexually transmitted infections (All: 3.3%, MAPD plan: 2.1%, commercial: 4.1%). The mean index treatment episode length was 297.0 days (MAPD plan: 283.6, commercial: 306.5). Total time on treatment was 477.3 days (MAPD plan: 450.7, commercial 496.0). At 3 months, 84.9% (MAPD plan: 83.6%, commercial: 85.8%) and at 12 months, 58.7% (MAPD plan: 57.2, commercial: 59.8) of patients achieved a PDC of at least 0.80. At 3 months, 100.0% (MAPD plan: 100.0%, commercial: 100.0%), and at 12 months, 74.3% (MAPD plan: 70.2%, commercial: 76.9%) of patients achieved a PDC of at least 0.60. The cohort had a mean of 16.4 fills of 30 days (MAPD plan: 16.4, commercial: 16.3) supply. CONCLUSIONS: There is an opportunity for clinical programs to focus on improving longer-term PrEP adherence among individuals at risk for HIV exposure.

Synthesis and comparison of iso-structural f-block metal complexes (Ce, U, Np, Pu) featuring η6-arene interactions.

Reaction of the terphenyl bis(anilide) ligand [{K(DME)2}2LAr] (LAr = {C6H4[(2,6-iPr2C6H3)NC6H4]2}2-) with trivalent chloride "MCl3" salts (M = Ce, U, Np) yields two distinct products; neutral LArM(Cl)(THF) (1M) (M = Np, Ce), and the "-ate" complexes [K(DME)2][(LAr)Np(Cl)2] (2Np) or ([LArM(Cl)2(µ-K(X)2)])∞ (2Ce, 2U) (M = Ce, U) (X = DME or Et2O) (2M). Alternatively, analogous reactions with the iodide [MI3(THF)4] salts provide access to the neutral compounds LArM(I)(THF) (3M) (M = Ce, U, Np, Pu). All complexes exhibit close arene contacts suggestive of η6-interactions with the central arene ring of the terphenyl backbone, with 3M comprising the first structurally characterized Pu η6-arene moiety. Notably, the metal-arene bond metrics diverge from the predicted trends of metal-carbon interactions based on ionic radii, with the uranium complexes exhibiting the shortest M-Ccentroid distance in all cases. Overall, the data presents a systematic study of f-element M-η6-arene complexes across the early actinides U, Np, Pu, and comparison to cerium congeners.

Mammographic Screening in Routine Practice: Multisite Study of Digital Breast Tomosynthesis and Digital Mammography Screenings.

Background The use of digital breast tomosynthesis (DBT) is increasing over digital mammography (DM) following studies demonstrating lower recall rates (RRs) and higher cancer detection rates (CDRs). However, inconsistent interpretation of evidence on the risks and benefits of mammography has resulted in varying screening mammography recommendations. Purpose To evaluate screening outcomes among women in the United States who underwent routine DM or DBT mammographic screening. Materials and Methods This retrospective cohort study included women aged 40-79 years who underwent DM or DBT screening mammograms between January 2014 and December 2020. Outcomes of RR, CDR, positive predictive value of recall (PPV1), biopsy rate, and positive predictive value of biopsy (PPV3) were compared between DM and DBT with use of adjusted multivariable logistic regression models. Results A total of 2 528 063 screening mammograms from 1 100 447 women (mean age, 57 years ± 10 [SD]) were included. In crude analyses, DBT (1 693 727 screening mammograms vs 834 336 DM screening mammograms) demonstrated lower RR (10.3% [95% CI: 10.3, 10.4] for DM vs 8.9% [95% CI: 8.9, 9.0] for DBT; P < .001) and higher CDR (4.5 of 1000 screening mammograms [95% CI: 4.3, 4.6] vs 5.3 of 1000 [95% CI: 5.2, 5.5]; P < .001), PPV1 (4.3% [95% CI: 4.2, 4.5] vs 5.9% [95% CI: 5.7, 6.0]; P < .001), and biopsy rates (14.5 of 1000 screening mammograms [95% CI: 14.2, 14.7] vs 17.6 of 1000 [95% CI: 17.4, 17.8]; P < .001). PPV3 was similar between cohorts (30.0% [95% CI: 29.2, 30.9] for DM vs 29.3% [95% CI: 28.7, 29.9] for DBT; P = .16). After adjustment for age, breast density, site, and index year, associations remained stable with respect to statistical significance. Conclusion Women undergoing digital breast tomosynthesis had improved screening mammography outcomes compared with women who underwent digital mammography. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Bae and Seo in this issue.

Assessment of a Claims-Based ICD-9 and ICD-10 Medication-Related Osteonecrosis of the Jaw Algorithm in the United States.

PURPOSE: Medication-related osteonecrosis of jaw (MRONJ) is associated with certain drug therapies. Pharmacoepidemiologic studies often rely on electronic healthcare data to assess adverse events following drug exposure. Few studies have developed and validated claims-based MRONJ identification algorithms. This study assessed the performance of claims-based MRONJ algorithms by chart review of potential cases among postmenopausal (PM) women and women with postmenopausal osteoporosis (PMO). METHODS: Among PM and PMO women sourced from a large US commercial health insurance database affiliated with Optum, potential cases were identified by International Classification of Diseases, 9th and 10th Revisions (ICD-9, ICD-10) diagnosis codes; 200 were selected for chart retrieval, with the goal of obtaining 100 charts in each coding era. Procured charts were redacted and then reviewed by an oral surgeon who determined case status. Positive predictive values (PPV) and 95% confidence intervals (CI) were calculated overall, by cohorts, and coding eras. Baseline characteristics were assessed. Two potential algorithm refinements were explored: using a restricted set of ICD codes; requiring antibiotic use after MRONJ diagnosis. RESULTS: A total of 1273 potential cases were identified. Of the 200 potential cases selected, 104 (52%) were procured, and six cases were confirmed (PPV 5.8%, 95% CI 2.2, 12.1). Baseline characteristics were largely similar across all strata. Potential algorithm refinements yielded marginal PPV improvement. CONCLUSION: This study identified a small number of confirmed cases, and the resulting PPVs were low, but consistent with reported studies. Potential algorithm refinements yielded minimal improvements. To our knowledge, this study is the first to report on the identification of MRONJ using ICD-10 codes in the US.

Isolation and characterization of a californium metallocene.

Californium (Cf) is currently the heaviest element accessible above microgram quantities. Cf isotopes impose severe experimental challenges due to their scarcity and radiological hazards. Consequently, chemical secrets ranging from the accessibility of 5f/6d valence orbitals to engage in bonding, the role of spin-orbit coupling in electronic structure, and reactivity patterns compared to other f elements, remain locked. Organometallic molecules were foundational in elucidating periodicity and bonding trends across the periodic table1-3, with a twenty-first-century renaissance of organometallic thorium (Th) through plutonium (Pu) chemistry4-12, and to a smaller extent americium (Am)13, transforming chemical understanding. Yet, analogous curium (Cm) to Cf chemistry has lain dormant since the 1970s. Here, we revive air-/moisture-sensitive Cf chemistry through the synthesis and characterization of [Cf(C5Me4H)2Cl2K(OEt2)]n from two milligrams of 249Cf. This bent metallocene motif, not previously structurally authenticated beyond uranium (U)14,15, contains the first crystallographically characterized Cf-C bond. Analysis suggests the Cf-C bond is largely ionic with a small covalent contribution. Lowered Cf 5f orbital energy versus dysprosium (Dy) 4f in the colourless, isoelectronic and isostructural [Dy(C5Me4H)2Cl2K(OEt2)]n results in an orange Cf compound, contrasting with the light-green colour typically associated with Cf compounds16-22.

Expanding the Nonaqueous Chemistry of Neptunium: Synthesis and Structural Characterization of [Np(NR2)3Cl], [Np(NR2)3Cl]-, and [Np{N(R)(SiMe2CH2)}2(NR2)]- (R = SiMe3).

Reaction of 3 equiv of NaNR2 (R = SiMe3) with NpCl4(DME)2 in THF afforded the Np(IV) silylamide complex, [Np(NR2)3Cl] (1), in good yield. Reaction of 1 with 1.5 equiv of KC8 in THF, in the presence of 1 equiv of dibenzo-18-crown-6, resulted in formation of [{K(DB-18-C-6)(THF)}3(µ3-Cl)][Np(NR2)3Cl]2 (4), also in good yield. Complex 4 represents the first structurally characterized Np(III) amide. Finally, reaction of NpCl4(DME)2 with 5 equiv of NaNR2 and 1 equiv of dibenzo-18-crown-6 afforded the Np(IV) bis(metallacycle), [{Na(DB-18-C-6)(Et2O)0.62(κ1-DME)0.38}2(µ-DME)][Np{N(R)(SiMe2CH2)}2(NR2)]2 (8), in moderate yield. Complex 8 was characterized by 1H NMR spectroscopy and X-ray crystallography and represents a rare example of a structurally characterized neptunium-hydrocarbyl complex. To support these studies, we also synthesized the uranium analogues of 4 and 8, namely, [K(2,2,2-cryptand)][U(NR2)3Cl] (2), [K(DB-18-C-6)(THF)2][U(NR2)3Cl] (3), [Na(DME)3][U{N(R)(SiMe2CH2)}2(NR2)] (6), and [{Na(DB-18-C-6)(Et2O)0.5(κ1-DME)0.5}2(µ-DME)][U{N(R)(SiMe2CH2)}2(NR2)]2 (7). Complexes 2, 3, 6, and 7 were characterized by a number of techniques, including NMR spectroscopy and X-ray crystallography.

Structural and Spectroscopic Comparison of Soft-Se vs. Hard-O Donor Bonding in Trivalent Americium/Neodymium Molecules.

Covalency is often considered to be an influential factor in driving An3+ vs. Ln3+ selectivity invoked by soft donor ligands. This is intensely debated, particularly the extent to which An3+ /Ln3+ covalency differences prevail and manifest as the f-block is traversed, and the effects of periodic breaks beyond Pu. Herein, two Am complexes, [Am{N(E=PPh2 )2 }3 ] (1-Am, E=Se; 2-Am, E=O) are compared to isoradial [Nd{N(E=PPh2 )2 }3 ] (1-Nd, 2-Nd) complexes. Covalent contributions are assessed and compared to U/La and Pu/Ce analogues. Through ab initio calculations grounded in UV-vis-NIR spectroscopy and single-crystal X-ray structures, we observe differences in f orbital involvement between Am-Se and Nd-Se bonds, which are not present in O-donor congeners.

Students report more positive attitudes toward older adults following an interprofessional service-learning course.

The aim of this study was to assess undergraduate students' perceptions of older adults over the semester in an interprofessional service-learning course that implemented a health promotion program called Bingocize® at community facilities for older adults. Students were surveyed at the beginning of the semester, at midterm, and at the conclusion of the course. Quantitative and qualitative data were collected to assess the students' perceptions and experiences. Results suggest that a course on aging that includes interprofessional service-learning in geriatric settings is associated with a significant increase in positive perceptions of the older adult population. Further research, however, is warranted to validate the findings.

Synthesis and Characterization of the {Si(NHCH2CH2NH)3[Mo(CO)3]2}2- Complex Comprising the Si(NHCH2CH2NH)32- Octahedron.

Reactions of K12Si17 with the low-valent transition-metal complex Mo(CO)3(C7H8) in ethylenediamine/toluene solutions in the presence of 2,2,2-cryptand yield the {Si(NHCH2CH2NH)3[Mo(CO)3]2}2- dianion, which contains an octahedral Si(NHCH2CH2NH)32- subunit. The SiN6 core comprises a rare example of a doubly deprotonated ethylenediame ligand in a coordination complex and is also the first structurally characterized example of a homoleptic Si(N∩N)3 trischelate. Its structure and spectroscopic properties are described.

Mechanistic Studies of [AlCp*]4 Combustion.

The combustion mechanism of [AlCp*]4 (Cp* = pentamethylcyclopentadienyl), a ligated aluminum(I) cluster, was studied by a combination of experimental and theoretical methods. Two complementary experimental methods, temperature-programmed reaction and T-jump time-of-flight mass spectrometry, were used to investigate the decomposition behaviors of [AlCp*]4 in both anaerobic and oxidative environments, revealing AlCp* and Al2OCp* to be the major decomposition products. The observed product distribution and reaction pathways are consistent with the prediction from molecular dynamics simulations and static density functional theory calculations. These studies demonstrated that experiment and theory can indeed serve as complementary and predictive means to study the combustion behaviors of ligated aluminum clusters and may help in engineering stable compounds as candidates for rocket propellants.

Sb@Ni12@Sb20-/+ and Sb@Pd12@Sb20n Cluster Anions, Where n = +1, -1, -3, -4: Multi-Oxidation-State Clusters of Interpenetrating Platonic Solids.

K5Sb4 and K3Sb7 Zintl ion precursors react with Pd(PPh3)4 in ethylenediamine/toluene/PBu4+ solutions to give crystals of Sb@Pd12@Sb20n-/PBu4+ salts, where n = 3, 4. The clusters are structurally identical in the two charge states, with nearly perfect Ih point symmetry, and can be viewed as an Sb@Pd12 icosahedron centered inside of an Sb20 dodecahedron. The metric parameters suggest very weak Sb-Sb and Pd-Pd interactions with strong radial Sb-Pd bonds between the Sb20 and Pd12 shells. All-electron DFT analysis shows the 3- ion to be diamagnetic with Ih symmetry and a 1.33 eV HOMO-LUMO gap, whereas the 4- ion undergoes a Jahn-Teller distortion to an S = 1/2 D3d structure with a small 0.1 eV gap. The distortion is predicted to be small and is not discernible by crystallography. Laser desorption-ionization time-of-flight mass spectrometry (LDI-TOF MS) studies of the crystalline samples show intense parent Sb@Pd12@Sb20- ions (negative ion mode) and Sb@Pd12@Sb20+ (positive ion mode) along with series of Sb@Pd12-y@Sb20-x-/+ ions. Ni(cyclooctadiene)2 reacts with K3Sb7 in en/tol/Bu4PBr solvent mixtures to give black precipitates of Sb@Ni12@Sb20n- salts that give similar Sb@Ni12@Sb20-/+ parent ions and Sb@Ni12-y@Sb20-x-/+ degradation series in the respective LDI-TOF MS studies. The solid-state and gas-phase studies of the icosahedral Sb@M12@Sb20n-/n+ ions show that the clusters can exist in the -4, -3, -1, +1 (M = Pd) and +1, -1 (M = Ni) oxidation states. These multiple-charge-state clusters are reminiscent of redox-active fullerenes (e.g., C60n, where n = +1, 0, -1, -2, -3, -4, -5, -6).

The plumbing of land surface models: is poor performance a result of methodology or data quality?

The PALS Land sUrface Model Benchmarking Evaluation pRoject (PLUMBER) illustrated the value of prescribing a priori performance targets in model intercomparisons. It showed that the performance of turbulent energy flux predictions from different land surface models, at a broad range of flux tower sites using common evaluation metrics, was on average worse than relatively simple empirical models. For sensible heat fluxes, all land surface models were outperformed by a linear regression against downward shortwave radiation. For latent heat flux, all land surface models were outperformed by a regression against downward shortwave, surface air temperature and relative humidity. These results are explored here in greater detail and possible causes are investigated. We examine whether particular metrics or sites unduly influence the collated results, whether results change according to time-scale aggregation and whether a lack of energy conservation in flux tower data gives the empirical models an unfair advantage in the intercomparison. We demonstrate that energy conservation in the observational data is not responsible for these results. We also show that the partitioning between sensible and latent heat fluxes in LSMs, rather than the calculation of available energy, is the cause of the original findings. Finally, we present evidence suggesting that the nature of this partitioning problem is likely shared among all contributing LSMs. While we do not find a single candidate explanation for why land surface models perform poorly relative to empirical benchmarks in PLUMBER, we do exclude multiple possible explanations and provide guidance on where future research should focus.