A Review of the Cost-Effectiveness Evidence for FDA-Approved Cell and Gene Therapies.

Cell and gene therapy (CGT) innovations have provided several significant breakthroughs in recent years. However, CGTs often come with a high upfront cost, raising questions about patient access, affordability, and long-term value. This study reviewed cost-effectiveness analysis (CEA) studies that have attempted to assess the long-term value of Food and Drug Administration (FDA)-approved CGTs. Two reviewers independently searched the Tufts Medical Center CEA Registry to identify all studies for FDA-approved CGTs, per January 2023. A data extraction template was used to summarize the evidence in terms of the incremental cost-effectiveness ratio expressed as the cost per quality-adjusted life year (QALY) and essential modeling assumptions, combined with a template to extract the adherence to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. The review identified 26 CEA studies for seven CGTs. Around half of the base-case cost-effectiveness results indicated that the cost per QALY was below $100,000-$150,000, often used as a threshold for reasonable cost-effectiveness in the United States. However, the results varied substantially across studies for the same treatment, ranging from being considered very cost-effective to far from cost-effective. Most models were based on data from single-arm trials with relatively short follow-ups, and different long-term extrapolations between studies caused large differences in the modeled cost-effectiveness results. In sum, this review showed that, despite the high upfront costs, many CGTs have cost-effectiveness evidence that can support long-term value. Nonetheless, substantial uncertainty regarding long-term value exists because so much of the modeling results are driven by uncertain extrapolations beyond the clinical trial data.

Recovery of Isoamyl Alcohol by Graphene Oxide Immobilized Membrane and Air-Sparged Membrane Distillation.

Isoamyl alcohol is an important biomass fermentation product that can be used as a gasoline surrogate, jet fuel precursor, and platform molecule for the synthesis of fine chemicals and pharmaceuticals. This study reports on the use of graphene oxide immobilized membra (GOIMs) for the recovery of isoamyl alcohol from an aqueous matrix. The separation was performed using air-sparged membrane distillation (ASMD). In contrast to a conventional PTFE membrane, which exhibited minimal separation, preferential adsorption on graphene oxide within GOIMs resulted in highly selective isoamyl alcohol separation. The separation factor reached 6.7, along with a flux as high as 1.12 kg/m2 h. Notably, the overall mass transfer coefficients indicated improvements with a GOIM. Optimization via response surfaces showed curvature effects for the separation factor due to the interaction effects. An empirical model was generated based on regression equations to predict the flux and separation factor. This study demonstrates the potential of GOIMs and ASMD for the efficient recovery of higher alcohols from aqueous solutions, highlighting the practical applications of these techniques for the production of biofuels and bioproducts.

Summarizing Implementation Support for School-Based COVID-19 Testing Programs in Southwest American Indian Communities.

CONTEXT: American Indian communities have been disproportionately affected by the COVID-19 pandemic, with school closures exacerbating health and education disparities. PROGRAM: Project SafeSchools' COVID-19 school-based testing program utilized federal and state funding to provide weekly pooled testing with follow-up rapid antigen testing to students and staff from the White Mountain Apache Tribe and Navajo Nation. IMPLEMENTATION: The project provided partner schools with training and continual logistical and technical support to aid in school-based testing and adherence to state and local reporting requirements. EVALUATION: Using the EPIS (Exploration, Preparation, Implementation, and Sustainment) framework, we identified facilitators and barriers to successful program function. While community support and buy-in were essential for successfully implementing school-based testing in these communities, communication, school staff turnover, and funding are among the most significant challenges. DISCUSSION: Community partnerships in American Indian communities involving schools and local health authorities can successfully implement testing protocols by remaining flexible and working together to maintain strong lines of communication.

A Trinuclear Gadolinium Cluster with a Three-Center One-Electron Bond and an S = 11 Ground State.

The recent discovery of metal-metal bonding and valence delocalization in the dilanthanide complexes (CpiPr5)2Ln2I3 (CpiPr5 = pentaisopropylcyclopentadienyl; Ln = Y, Gd, Tb, Dy) opened up the prospect of harnessing the 4fn5dz21 electron configurations of non-traditional divalent lanthanide ions to access molecules with novel bonding motifs and magnetism. Here, we report the trinuclear mixed-valence clusters (CpiPr5)3Ln3H3I2 (1-Ln, Ln = Y, Gd), which were synthesized via potassium graphite reduction of the trivalent clusters (CpiPr5)3Ln3H3I3. Structural, computational, and spectroscopic analyses support valence delocalization in 1-Ln resulting from a three-center, one-electron σ bond formed from the 4dz2 and 5dz2 orbitals on Y and Gd, respectively. Dc magnetic susceptibility data obtained for 1-Gd reveal that valence delocalization engenders strong parallel alignment of the σ-bonding electron and the 4f electrons of each gadolinium center to afford a high-spin ground state of S = 11. Notably, this represents the first clear instance of metal-metal bonding in a molecular trilanthanide complex, and the large spin-spin exchange constant of J = 168(1) cm-1 determined for 1-Gd is only the second largest coupling constant characterized to date for a molecular lanthanide compound.

Divalent Lanthanide Metallocene Complexes with a Linear Coordination Geometry and Pronounced 6s-5d Orbital Mixing.

A small but growing number of molecular compounds have been isolated featuring divalent lanthanides with 4fn5dz21 electron configurations. While the majority of these possess trigonal coordination geometries, we previously reported the first examples of linear divalent metallocenes Ln(CpiPr5)2 (Ln = Tb, Dy; CpiPr5 = pentaisopropylcyclopentadienyl). Here, we report the synthesis and characterization of the remainder of the Ln(CpiPr5)2 (1-Ln) series (including Y and excluding Pm). The compounds can be synthesized through salt metathesis of LnI3 and NaCpiPr5 followed by potassium graphite reduction for Ln = Y, La, Ce, Pr, Nd, Gd, Ho, and Er, by in situ reduction during salt metathesis of LnI3 and NaCpiPr5 for Ln = Tm and Lu, or through salt metathesis from LnI2 and NaCpiPr5 for Ln = Sm, Eu, and Yb. Single crystal X-ray diffraction analyses of 1-Ln confirm a linear coordination geometry with pseudo-D5d symmetry for the entire series. Structural and ultraviolet-visible spectroscopy data support a 4fn+1 electron configuration for Ln2+ = Sm, Eu, Tm, and Yb and a 4fn5dz21 configuration for the other lanthanides ([Kr]4dz21 for Y2+). Characterization of 1-Ln (Ln = Y, La) using electron paramagnetic resonance spectroscopy reveals significant s-d orbital mixing in the highest occupied molecular orbital and hyperfine coupling constants that are the largest reported to date for divalent compounds of yttrium and lanthanum. Evaluation of the room temperature magnetic susceptibilities of 1-Ln and comparison with values previously reported for trigonal Ln2+ compounds suggests that the more pronounced 6s-5d mixing may be associated with weaker 4f-5d spin coupling.

Plasma proteome analyses in individuals of European and African ancestry identify cis-pQTLs and models for proteome-wide association studies.

Improved understanding of genetic regulation of the proteome can facilitate identification of the causal mechanisms for complex traits. We analyzed data on 4,657 plasma proteins from 7,213 European American (EA) and 1,871 African American (AA) individuals from the Atherosclerosis Risk in Communities study, and further replicated findings on 467 AA individuals from the African American Study of Kidney Disease and Hypertension study. Here, we identified 2,004 proteins in EA and 1,618 in AA, with most overlapping, which showed associations with common variants in cis-regions. Availability of AA samples led to smaller credible sets and notable number of population-specific cis-protein quantitative trait loci. Elastic Net produced powerful models for protein prediction in both populations. An application of proteome-wide association studies to serum urate and gout implicated several proteins, including IL1RN, revealing the promise of the drug anakinra to treat acute gout flares. Our study demonstrates the value of large and diverse ancestry study to investigate the genetic mechanisms of molecular phenotypes and their relationship with complex traits.

Ultrahard magnetism from mixed-valence dilanthanide complexes with metal-metal bonding.

Magnetic effects of lanthanide bonding Lanthanide coordination compounds have attracted attention for their persistent magnetic properties near liquid nitrogen temperature, well above alternative molecular magnets. Gould et al. report that introducing metal-metal bonding can enhance coercivity. Reduction of iodide-bridged terbium or dysprosium dimers resulted in a single electron bond between the metals, which enforced alignment of the other valence electrons. The resultant coercive fields exceeded 14 tesla below 50 and 60 kelvin for the terbium and dysprosium compounds, respectively. ­JSY

Solvent-free dehydration, cyclization, and hydrogenation of linalool with a dual heterogeneous catalyst system to generate a high-performance sustainable aviation fuel.

The development of efficient catalytic methods for the synthesis of bio-based, full-performance jet fuels is critical for limiting the impacts of climate change while enabling a thriving modern society. To help address this need, here, linalool, a terpene alcohol that can be produced via fermentation of biomass sugars, was dehydrated, cyclized, and hydrogenated in a one-pot reaction under moderate reaction conditions. This sequence produced a biosynthetic fuel mixture primarily composed of 1-methyl-4-isopropylcyclohexane (p-menthane) and 2,6-dimethyloctane (DMO). The reaction was promoted by a catalyst composed of commercial Amberlyst-15, H+ form, and 10% Pd/C. Two other terpenoid substrates (1,8-cineole and 1,4-cineole) were subjected to the same conditions and excellent conversion to high purity p-menthane was observed. The fuel mixture derived from linalool exhibits a 1.7% higher gravimetric heat of combustion and 66% lower kinematic viscosity at -20 °C compared to the limits for conventional jet fuel. These properties suggest that isomerized hydrogenated linalool (IHL) can be blended with conventional jet fuel or synthetic paraffinic kerosenes to deliver high-performance sustainable aviation fuels for commercial and military applications.

Synthesis of Bio-Based Methylcyclopentadiene from 2,5-Hexanedione: A Sustainable Route to High Energy Density Jet Fuels.

The sustainable, bio-based, platform chemical, 2,5-hexanedione [HD (1)], was efficiently converted to methylcyclopentadiene [MCPD (4)] through a three-step process consisting of intramolecular aldol condensation, catalytic chemoselective hydrogenation, and dehydration. Base-catalyzed aldol condensation of 1 resulted in the formation of 3-methyl-2-cyclopenten-1-one [MCO (2)], which was then converted to 3-methyl-2-cyclopenten-1-ol [MCP (3)] by chemoselective reduction with a ternary Ru catalyst system [RuCl2 (PPh3 )3 /NH2 (CH2 )2 NH2 /KOH]. The hydrogenation proceeded with 96 % chemoselectivity. 3 was then dehydrated over AlPO4 /MgSO4 at 70 °C under reduced pressure to yield 4, which can undergo an ambient temperature [4+2]-Diels-Alder cyclization to generate dimethyldicyclopentadiene (DMDCPD), a commodity chemical useful for the preparation of high-performance fuels and polymers. Through this approach, advanced jet fuels and materials can be conveniently produced from sustainable cellulosic feedstocks.

Individual and community-level risk for COVID-19 mortality in the United States.

Reducing COVID-19 burden for populations will require equitable and effective risk-based allocations of scarce preventive resources, including vaccinations1. To aid in this effort, we developed a general population risk calculator for COVID-19 mortality based on various sociodemographic factors and pre-existing conditions for the US population, combining information from the UK-based OpenSAFELY study with mortality rates by age and ethnicity across US states. We tailored the tool to produce absolute risk estimates in future time frames by incorporating information on pandemic dynamics at the community level. We applied the model to data on risk factor distribution from a variety of sources to project risk for the general adult population across 477 US cities and for the Medicare population aged 65 years and older across 3,113 US counties, respectively. Validation analyses using 54,444 deaths from 7 June to 1 October 2020 show that the model is well calibrated for the US population. Projections show that the model can identify relatively small fractions of the population (for example 4.3%) that might experience a disproportionately large number of deaths (for example 48.7%), but there is wide variation in risk across communities. We provide a web-based risk calculator and interactive maps for viewing community-level risks.

Bio-Based Cycloalkanes: The Missing Link to High-Performance Sustainable Jet Fuels.

Invited for this month's cover is the group of Ben Harvey at the Naval Air Warfare Center, Weapons Division, China Lake. The image shows several examples of bio-based cycloalkanes that have been developed as next-generation sustainable jet fuels. The Review itself is available at 10.1002/cssc.202001641.

Bio-Based Cycloalkanes: The Missing Link to High-Performance Sustainable Jet Fuels.

The development of sustainable energy solutions that reduce global carbon emissions, while maintaining high living standards, is one of the grand challenges of the current century. Transportation fuels are critical to economic development, globalization, and the advancement of society. Although ground vehicles and small aircraft are beginning a slow transition toward electric propulsion with energy sourced from solar radiation or wind, the extreme power requirements of jet aircraft require a more concentrated source of energy that is conveniently provided by liquid hydrocarbon fuels. This Review describes recent efforts to develop efficient routes for the conversion of crude biomass sources (e. g., lignocellulose) to cycloalkanes. These cycloalkanes impart advantageous properties to jet fuels, including increased density, higher volumetric heat of combustion, and enhanced operability. The combination of bio-based cycloalkanes and synthetic paraffinic kerosenes allows for the preparation of 100 % bio-based fuels that can outperform conventional petroleum-based fuels. In this Review methods are described that convert biomass-derived small molecules, including furfural, furfuryl alcohol, 5-hydroxymethylfurfural, cyclic ketones, phenolics, acyclic ketones, cyclic alcohols, furans, esters, and alkenes to high-density cycloalkanes. In addition to describing the chemical transformations and catalysts that have been developed to efficiently produce various cycloalkanes, this Review includes summaries of key fuel properties, which highlight the ability to generate fuels with customized performance metrics. This work is intended to inspire other researchers to study the conversion of sustainable feedstocks to full-performance aviation fuels. An acceleration of this research is critical to reducing the carbon footprint of commercial and military aviation on a timescale that will help blunt the impacts of global warming.

Synthesis and Magnetism of Neutral, Linear Metallocene Complexes of Terbium(II) and Dysprosium(II).

The divalent metallocene complexes Ln(CpiPr5)2 (Ln = Tb, Dy) were synthesized through the KC8 reduction of Ln(CpiPr5)2I intermediates and represent the first examples of neutral, linear metallocenes for these elements. X-ray diffraction analysis, density functional theory calculations, and magnetic susceptibility measurements indicate a 4fn5d1 electron configuration with strong s/d mixing that supports the linear coordination geometry. A comparison of the magnetic relaxation behavior of the two divalent metallocenes relative to salts of their trivalent counterparts, [Ln(CpiPr5)2][B(C6F5)4], reveals that lanthanide reduction has opposing effects for dysprosium and terbium, with magnetic relaxation times increasing from TbIII to TbII and decreasing from DyIII to DyII. The impact of this effect is most notably evident for Tb(CpiPr5)2, which displays an effective thermal barrier to magnetic relaxation of 1205 cm-1 and a 100-s blocking temperature of 52 K, the highest values yet observed for any nondysprosium single-molecule magnet.

High-Performance Jet Fuels Derived from Bio-Based Alkenes by Iron-Catalyzed [2+2] Cycloaddition.

A series of high-performance cycloparaffinic fuels have been generated by [2+2] cycloaddition of the bio-derived alkenes 1-hexene, isoprene, and 1-pentene, catalyzed by a low-valent iron pyridine(diimine) complex [(Me PDI)Fe(N2 )2 (µ-N2 )] [Me PDI=N,N'-(2,6-pyridinediyldiethylidyne)bis(2,6-dimethylbenzenamine)]. Reactions with 1-pentene and 1-hexene resulted in 85 % selectivity to 1,2-cyclobutanes, and 12 % selectivity to acyclic alkenes generated by ß-hydride elimination. Self-dimerization of isoprene was sluggish and generated heavier oligomer products, but cross-dimerization of isoprene with 1-hexene afforded primarily a 1,3-cyclobutane product, along with isomers of acyclic C11 mixed dimers. Hydrocarbon mixtures were hydrogenated and fractionally distilled to yield finished fuel mixtures in overall yields of 83-93 % at the multigram scale. The fuels exhibited densities ranging between 0.767 and 0.783 g mL-1 , and net heats of combustion (NHOC) of up to 120.6 kBtu gal-1 (43.8 MJ kg-1 ). These values are higher than conventional synthetic paraffinic kerosenes owing to the higher density and ring strain afforded by the cyclobutane rings. The fuel mixtures also exhibited extremely low viscosities ranging from 2.38 to 4.78 mm2 s-1 at -20 °C, due in part to the presence of the acyclic dimers. The excellent fuel properties of the product mixtures, selectivity for dimer products, high yields, and the ability to use simple bio-derived alkenes as substrates, make the [Fe]-catalyzed [2+2] cycloaddition of unactivated alkenes a compelling route to the synthesis of sustainable high-performance fuels.

[4+4]-Cycloaddition of Isoprene for the Production of High-Performance Bio-Based Jet Fuel.

Isoprene was efficiently converted to 1,6-dimethyl-1,5-cyclooctadiene (DMCOD) by selective [4+4]-cycloaddition with a catalyst formed by in situ reduction of [(MePI)FeCl(µ-Cl)]2 (MePI = [2-(2,6-(CH3)2-C6H3-N=C(CH3))-C4H5N]). DMCOD was isolated in 92% yield, at the preparative scale, with a catalyst loading of 0.025 mol%, and a TON of 3680. Catalytic hydrogenation of DMCOD yielded 1,4-dimethylcyclooctane (DMCO). The cyclic structure and ring strain of DMCO afforded gravimetric and volumetric net heats of combustion 2.4 and 9.2% higher, respectively, than conventional jet fuel. In addition, the presence of methyl branches at two sites resulted in a -20 °C kinematic viscosity of 4.17 mm2 s-1, 48 % lower than the maximum allowed value for conventional jet fuel. The ability to derive isoprene and related alcohols readily from abundant biomass sources, coupled with the highly efficient [Fe]-catalyzed [4+4]-cycloaddition described herein, suggests that this process holds great promise for the economical production of high-performance, bio-based jet fuel blendstocks.

High-temperature magnetic blocking and magneto-structural correlations in a series of dysprosium(iii) metallocenium single-molecule magnets.

A series of dysprosium(iii) metallocenium salts, [Dy(CpiPr4R)2][B(C6F5)4] (R = H (1), Me (2), Et (3), iPr (4)), was synthesized by reaction of DyI3 with the corresponding known NaCpiPr4R (R = H, iPr) and novel NaCpiPr4R (R = Me, Et) salts at high temperature, followed by iodide abstraction with [H(SiEt3)2][B(C6F5)4]. Variation of the substituents in this series results in substantial changes in molecular structure, with more sterically-encumbering cyclopentadienyl ligands promoting longer Dy-C distances and larger Cp-Dy-Cp angles. Dc and ac magnetic susceptibility data reveal that these structural changes have a considerable impact on the magnetic relaxation behavior and operating temperature of each compound. In particular, the magnetic relaxation barrier increases as the Dy-C distance decreases and the Cp-Dy-Cp angle increases. An overall 45 K increase in the magnetic blocking temperature is observed across the series, with compounds 2-4 exhibiting the highest 100 s blocking temperatures yet reported for a single-molecule magnet. Compound 2 possesses the highest operating temperature of the series with a 100 s blocking temperature of 62 K. Concomitant increases in the effective relaxation barrier and the maximum magnetic hysteresis temperature are observed, with 2 displaying a barrier of 1468 cm-1 and open magnetic hysteresis as high as 72 K at a sweep rate of 3.1 mT s-1. Magneto-structural correlations are discussed with the goal of guiding the synthesis of future high operating temperature DyIII metallocenium single-molecule magnets.

Galantamine is not a positive allosteric modulator of human α4ß2 or α7 nicotinic acetylcholine receptors.

BACKGROUND AND PURPOSE: The alkaloid galantamine was originally isolated from the green snowdrop Galanthus woronowii and is currently marketed as a drug for treatment of mild to moderate dementia in patients with Alzheimer's disease. In addition to a well-documented proficiency to inhibit acetylcholinesterase, galantamine has been reported to increase neuronal nicotinic ACh (nACh) receptor function by acting as a positive allosteric modulator. Yet there remains controversy regarding these findings in the literature. To resolve this conundrum, we evaluated galantamine actions at α4ß2 and α7, which represent the nACh receptors most commonly associated with mammalian cognitive domains. EXPERIMENTAL APPROACH: α4ß2 [in (α4)3 (ß2)2 and (α4)2 (ß2)3 stoichiometries] and α7 nACh receptors were expressed in Xenopus laevis oocytes and subjected to two-electrode voltage-clamp electrophysiological experiments. Galantamine (10 nM to 100 µM) was evaluated for direct agonist effects and for positive modulation by co-application with sub-maximally efficacious concentrations of ACh. In addition, similar experiments were performed with α7 nACh receptors stably expressed in HEK293 cells using patch-clamp electrophysiology. KEY RESULTS: In concentrations ranging from 10 nM to 1 µM, galantamine did not display direct agonism nor positive modulatory effects at any receptor combination tested. At concentrations from 10 µM and above, galantamine inhibited the activity with a mechanism of action consistent with open-channel pore blockade at all receptor types. CONCLUSION AND IMPLICATIONS: Based on our data, we conclude that galantamine is not a positive allosteric modulator of α7 or α4ß2 receptors, which represent the majority of nACh receptors in mammalian brain.

Cloud-Scale Genomic Signals Processing for Robust Large-Scale Cancer Genomic Microarray Data Analysis.

As microarray data available to scientists continues to increase in size and complexity, it has become overwhelmingly important to find multiple ways to bring forth oncological inference to the bioinformatics community through the analysis of large-scale cancer genomic (LSCG) DNA and mRNA microarray data that is useful to scientists. Though there have been many attempts to elucidate the issue of bringing forth biological interpretation by means of wavelet preprocessing and classification, there has not been a research effort that focuses on a cloud-scale distributed parallel (CSDP) separable 1-D wavelet decomposition technique for denoising through differential expression thresholding and classification of LSCG microarray data. This research presents a novel methodology that utilizes a CSDP separable 1-D method for wavelet-based transformation in order to initialize a threshold which will retain significantly expressed genes through the denoising process for robust classification of cancer patients. Additionally, the overall study was implemented and encompassed within CSDP environment. The utilization of cloud computing and wavelet-based thresholding for denoising was used for the classification of samples within the Global Cancer Map, Cancer Cell Line Encyclopedia, and The Cancer Genome Atlas. The results proved that separable 1-D parallel distributed wavelet denoising in the cloud and differential expression thresholding increased the computational performance and enabled the generation of higher quality LSCG microarray datasets, which led to more accurate classification results.

Experimental Data Extraction and in Silico Prediction of the Estrogenic Activity of Renewable Replacements for Bisphenol A.

Bisphenol A (BPA) is a ubiquitous compound used in polymer manufacturing for a wide array of applications; however, increasing evidence has shown that BPA causes significant endocrine disruption and this has raised public concerns over safety and exposure limits. The use of renewable materials as polymer feedstocks provides an opportunity to develop replacement compounds for BPA that are sustainable and exhibit unique properties due to their diverse structures. As new bio-based materials are developed and tested, it is important to consider the impacts of both monomers and polymers on human health. Molecular docking simulations using the Estrogenic Activity Database in conjunction with the decision forest were performed as part of a two-tier in silico model to predict the activity of 29 bio-based platform chemicals in the estrogen receptor-α (ERα). Fifteen of the candidates were predicted as ER binders and fifteen as non-binders. Gaining insight into the estrogenic activity of the bio-based BPA replacements aids in the sustainable development of new polymeric materials.

Renewable Gasoline, Solvents, and Fuel Additives from 2,3-Butanediol.

2,3-Butanediol (2,3-BD) is a renewable alcohol that can be prepared in high yield from biomass sugars. 2,3-BD was selectively dehydrated in a solvent-free process to a complex mixture of 2-ethyl-2,4,5-trimethyl-1,3-dioxolanes and 4,5-dimethyl-2isopropyl dioxolanes with the heterogeneous acid catalyst Amberlyst-15. The purified dioxolane mixture exhibited an anti-knock index of 90.5, comparable to high octane gasoline, and a volumetric net heat of combustion 34 % higher than ethanol. The solubility of the dioxolane mixture in water was only 0.8 g per 100 mL, nearly an order of magnitude lower than the common gasoline oxygenate methyl tert-butyl ether. The dioxolane mixture has potential applications as a sustainable gasoline blending component, diesel oxygenate, and industrial solvent.