New Estimates on the Cost of a Delay Day in Drug Development.

Two frequently cited figures by clinical research insiders and observers - the cost of missing a day to generate prescription drug sales and the cost of a day to conduct a clinical trial - are outdated and based on anecdotal evidence. In late 2023, the Tufts Center for the Study of Drug Development conducted empirical research to gather more accurate and granular estimates and to test whether average sales per day have changed over time. 645 drugs launched since 2000, and 409 clinical trial budgets were drawn from commercially available and proprietary data sets and analyzed. The results indicate that a single day equals approximately $500,000 in lost prescription drug or biologic sales, with daily prescription sales for infectious, hematologic, cardiovascular, and gastrointestinal diseases among the highest. The results also show that each year, the average sales per day of prescription drugs and biologics has decreased by approximately $80,000-$100,000. The estimated direct daily cost to conduct a clinical trial is approximately $40,000 per day for phase II and III clinical trials, with those in respiratory, rheumatology, and dermatology having the highest relative daily direct costs.

Single Layer Silk and Cotton Woven Fabrics for Acoustic Emission and Active Sound Suppression.

Whether intentionally generating acoustic waves or attempting to mitigate unwanted noise, sound control is an area of challenge and opportunity. This study investigates traditional fabrics as emitters and suppressors of sound. When attached to a single strand of a piezoelectric fiber actuator, a silk fabric emits up to 70 dB of sound. Despite the complex fabric structure, vibrometer measurements reveal behavior reminiscent of a classical thin plate. Fabric pore size relative to the viscous boundary layer thickness is found-through comparative fabric analysis-to influence acoustic-emission efficiency. Sound suppression is demonstrated using two distinct mechanisms. In the first, direct acoustic interference is shown to reduce sound by up to 37 dB. The second relies on pacifying the fabric vibrations by the piezoelectric fiber, reducing the amplitude of vibration waves by 95% and attenuating the transmitted sound by up to 75%. Interestingly, this vibration-mediated suppression in principle reduces sound in an unlimited volume. It also allows the acoustic reflectivity of the fabric to be dynamically controlled, increasing by up to 68%. The sound emission and suppression efficiency of a 130 µm silk fabric presents opportunities for sound control in a variety of applications ranging from apparel to transportation to architecture.

Penetrant-induced plasticization in microporous polymer membranes.

Penetrant-induced plasticization has prevented the industrial deployment of many polymers for membrane-based gas separations. With the advent of microporous polymers, new structural design features and unprecedented property sets are now accessible under controlled laboratory conditions, but property sets can often deteriorate due to plasticization. Therefore, a critical understanding of the origins of plasticization in microporous polymers and the development of strategies to mitigate this effect are needed to advance this area of research. Herein, an integrative discussion is provided on seminal plasticization theory and gas transport models, and these theories and models are compared to an exhaustive database of plasticization characteristics of microporous polymers. Correlations between specific polymer properties and plasticization behavior are presented, including analyses of plasticization pressures from pure-gas permeation tests and mixed-gas permeation tests for pure polymers and composite films. Finally, an evaluation of common and current state-of-the-art strategies to mitigate plasticization is provided along with suggestions for future directions of fundamental and applied research on the topic.

Effects of alerting signals on the spatial Stroop effect: evidence for modality differences.

Reaction times and error rates to a target's identity are impaired when the target is presented in a location that mismatches the response required, relative to situations where the location of the target and required response overlap (the Simon effect) and the same is true when the target's identity conveys spatial information (the spatial Stroop effect). Prior studies have found that visual versions of the spatial Stroop effect are magnified when alerting cues appear before the target and results are consistent with a dual-route framework where alerting cues boost automatic stimulus-response motor associations through the direct processing route. However, the influence of alerting signals on auditory versions of the spatial Stroop effect have not been tested and there are reasons to believe that the alerting-congruency interaction may differ across stimulus modality. In two experiments the effects of alerting cues on auditory (Experiment 1; N = 98) and visual (Experiment 2; N = 97) spatial Stroop effects are examined. Results show that alerting cues boost the spatial Stroop effect with visual stimuli but not auditory stimuli and a distributional analysis provides support for there being modality differences in the decay (or inhibition) of response-code activation. Implications for explanations of the alerting-congruence interaction are discussed.

A Microporous Poly(Arylene Ether) Platform for Membrane-Based Gas Separation.

Membrane-based gas separations are crucial for an energy-efficient future. However, it is difficult to develop membrane materials that are high-performing, scalable, and processable. Microporous organic polymers (MOPs) combine benefits for gas sieving and solution processability. Herein, we report membrane performance for a new family of microporous poly(arylene ether)s (PAEs) synthesized via Pd-catalyzed C-O coupling reactions. The scaffold of these microporous polymers consists of rigid three-dimensional triptycene and stereocontorted spirobifluorene, endowing these polymers with micropore dimensions attractive for gas separations. This robust PAE synthesis method allows for the facile incorporation of functionalities and branched linkers for control of permeation and mechanical properties. A solution-processable branched polymer was formed into a submicron film and characterized for permeance and selectivity, revealing lab data that rivals property sets of commercially available membranes already optimized for much thinner configurations. Moreover, the branching motif endows these materials with outstanding plasticization resistance, and their microporous structure and stability enables benefits from competitive sorption, increasing CO2 /CH4 and (H2 S+CO2 )/CH4 selectivity in mixture tests as predicted by the dual-mode sorption model. The structural tunability, stability, and ease-of-processing suggest that this new platform of microporous polymers provides generalizable design strategies to form MOPs at scale for demanding gas separations in industry.

PolyMOF nanoparticles constructed from intrinsically microporous polymer ligand towards scalable composite membranes for CO2 separation.

Integrating different modification strategies into a single step to achieve the desired properties of metal-organic frameworks (MOFs) has been very synthetically challenging, especially in developing advanced MOF/polymer mixed matrix membranes (MMMs). Herein, we report a polymer-MOF (polyMOF) system constructed from a carboxylated polymer with intrinsic microporosity (cPIM-1) ligand. This intrinsically microporous ligand could coordinate with metals, leading to ~100 nm-sized polyMOF nanoparticles. Compared to control MOFs, these polyMOFs exhibit enhanced ultramicroporosity for efficient molecular sieving, and they have better dispersion properties in casting solutions to prepare MMMs. Ultimately, integrating coordination chemistries through the cPIM-1 and polymer-based functionality into porous materials results in polyMOF/PIM-1 MMMs that display excellent CO2 separation performance (surpassing the CO2/N2 and CO2/CH4 upper bounds). In addition to exploring the physicochemical and transport properties of this polyMOF system, scalability has been demonstrated by converting the developed MMM material into large-area (400 cm2) thin-film nanocomposite (TFN) membranes.

Engineering the Polymer-MOF Interface in Microporous Composites to Address Complex Mixture Separations.

Poor interfacial compatibility remains a pressing challenge in the fabrication of high-performance polymer-MOF composites. In response, introducing compatible chemistries such as a carboxylic acid moiety has emerged as a compelling strategy to increase polymer-MOF interactions. In this work, we leveraged compatible functionalities in UiO-66-NH2 and a carboxylic acid-functionalized PIM-1 to fabricate mixed-matrix membranes (MMMs) with improved separation performance compared to PIM-1-based MMMs in industrially relevant conditions. Under pure-gas conditions, PIM-COOH-based MMMs retained selectivity with increasing MOF loading and showed increased permeability due to increased diffusion. The composites were further investigated under industrially relevant conditions, including CO2/N2, CO2/CH4, and H2S/CO2/CH4 mixtures, to elucidate the effects of competitive sorption and plasticization. Incorporation of UiO-66-NH2 in PIM-COOH and PIM-1 mitigated the effects of CO2- and H2S-induced plasticization typically observed in linear polymers. In CO2-based binary mixed-gas tests, all samples showed similar performance as that in pure-gas tests, with minimal competitive sorption contributions associated with the amine functional groups of the MOF. In ternary mixed-gas tests, improved plasticization resistance and interfacial compatibility resulted in PIM-COOH-based MMMs having the highest H2S/CH4 and CO2/CH4 selectivity combinations among the films tested in this study. These findings demonstrate that selecting MOFs and polymers with compatible functional groups is a useful strategy in developing high-performing microporous MMMs that require stability under complex and industrially relevant conditions.

Uncertainty in Composite Membranes: From Defect Engineering to Film Processing.

Composite membranes featuring metal-organic framework (MOF)-dispersed polymers have attracted tremendous attention in recent years. However, evaluating commercial viability is oftentimes obscured by the irreproducibility in both MOF synthesis and film manufacturing protocols. Variability in MOF property sets are typically ascribed to crystal defects resulting from subtle variations in synthesis, but quantitative studies investigating the role of defects on transport properties are exceedingly rare. Likewise, controlled film formation protocols are rarely reported in the open literature, making it difficult to provide substantial and informative structure-property correlations. This study aims to address these uncertainties. To this end, two samples of a prototypical MOF, UiO-66-NH2, were synthesized to feature similar particle size, morphology, and colloidal stability. However, defect engineering protocols coupled with careful screening experiments were developed to synthesize the two MOFs with maximally different porosities. Composite membranes were prepared for each MOF and a high-performance polymer, 6FDA-Durene, and then tested for light gas permeation measurements, revealing a small and unexpected enhancement in CO2/CH4 performance for samples containing low-porosity UiO-66-NH2. Mechanistic studies on sorption revealed a surprising 50% decrease in sorption capacity for high-porosity UiO-66-NH2, completely offsetting enhancements from increased gas diffusion. By using multiple replicate experiments, the sample-to-sample variation was large enough to obscure any differences in permeability and selectivity between the two types of MOF composites at low volume fractions. Application of the Maxwell model to extrapolate pure-MOF performance led to significant variations in predicted values, demonstrating the importance of collecting and reporting replicate experiments for membrane preparation and testing.

Side-Chain Length and Dispersity in ROMP Polymers with Pore-Generating Side Chains for Gas Separations.

Bottlebrush polymers with flexible backbones and rigid side chains have shown ultrahigh CO2 permeability and plasticization resistance for membrane-based gas separations. To date, this class of polymers has only been studied with polydisperse side chains. Herein, we report gas transport properties of a methoxy (OMe) functionalized polymer synthesized via ring-opening metathesis polymerization (ROMP) with uniform side-chain lengths ranging from n = 2 to 5 repeat units to elucidate the role of both side-chain length and dispersity on gas transport properties and plasticization resistance. As side-chain length increased, both Brunauer-Emmett-Teller (BET) surface area and gas permeability increased with minimal losses in gas selectivity. Increased plasticization resistance was also observed with increasing side-chain length, which can be attributed to increased interchain rigidity from longer side chains. Controlling the side-chain length provides an effective strategy to rationally control and optimize the performance of ROMP polymers for CO2-based gas separations.

Hydrocarbon ladder polymers with ultrahigh permselectivity for membrane gas separations.

Membranes have the potential to substantially reduce energy consumption of industrial chemical separations, but their implementation has been limited owing to a performance upper bound-the trade-off between permeability and selectivity. Although recent developments of highly permeable polymer membranes have advanced the upper bounds for various gas pairs, these polymers typically exhibit limited selectivity. We report a class of hydrocarbon ladder polymers that can achieve both high selectivity and high permeability in membrane separations for many industrially relevant gas mixtures. Additionally, their corresponding films exhibit desirable mechanical and thermal properties. Tuning of the ladder polymer backbone configuration was found to have a profound effect on separation performance and aging behavior.

Leveraging Free Volume Manipulation to Improve the Membrane Separation Performance of Amine-Functionalized PIM-1.

Gas-separation polymer membranes display a characteristic permeability-selectivity trade-off that has limited their industrial use. The most comprehensive approach to improving performance is to devise strategies that simultaneously increase fractional free volume, narrow free volume distribution, and enhance sorption selectivity, but generalizable methods for such approaches are exceedingly rare. Here, we present an in situ crosslinking and solid-state deprotection method to access previously inaccessible sorption and diffusion characteristics in amine-functionalized polymers of intrinsic microporosity. Free volume element (FVE) size can be increased while preserving a narrow FVE distribution, enabling below-upper bound polymers to surpass the H2 /N2 , H2 /CH4 , and O2 /N2 upper bounds and improving CO2 -based selectivities by 200 %. This approach can transform polymers into chemical analogues with improved performance, thereby overcoming traditional permeability-selectivity trade-offs.

The disutility of stress testing in low-risk HEART Pathway patients.

BACKGROUND: The HEART Pathway identifies low-risk chest pain patients for discharge from the Emergency Department without stress testing. However, HEART Pathway recommendations are not always followed. The objective of this study is to determine the frequency and diagnostic yield of stress testing among low-risk patients. METHODS: An academic hospital's chest pain registry was analyzed for low-risk HEART Pathway patients (HEAR score ≤ 3 with non-elevated troponins) from 1/2017 to 7/2018. Stress tests were reviewed for inducible ischemia. Diagnostic yield was defined as the rate of obstructive CAD among patients with positive stress testing. T-test or Fisher's exact test was used to test the univariate association of age, sex, race/ethnicity, and HEAR score with stress testing. Multivariate logistic regression was used to determine the association of age, sex, race/ethnicity, and HEAR score with stress testing. RESULTS: There were 4743 HEART Pathway assessments, with 43.7% (2074/4743) being low-risk. Stress testing was performed on 4.1% (84/2074). Of the 84 low-risk patients who underwent testing, 8.3% (7/84) had non-diagnostic studies and 2.6% (2/84) had positive studies. Among the 2 patients with positive studies, angiography revealed that 1 had widely patent coronary arteries and the other had multivessel obstructive coronary artery disease, making the diagnostic yield of stress testing 1.2% (1/84). Each one-point increase in HEAR score (aOR 2.17, 95% CI 1.45-3.24) and being male (aOR 1.59, 95% CI 1.02-2.49) were associated with testing. CONCLUSIONS: Stress testing among low-risk HEART Pathway patients was uncommon, low yield, and more likely in males and those with a higher HEAR score.

Tuning Selectivities in Gas Separation Membranes Based on Polymer-Grafted Nanoparticles.

Polymer membranes are critical to many sustainability applications that require the size-based separation of gas mixtures. Despite their ubiquity, there is a continuing need to selectively affect the transport of different mixture components while enhancing mechanical strength and hindering aging. Polymer-grafted nanoparticles (GNPs) have recently been explored in the context of gas separations. Membranes made from pure GNPs have higher gas permeability and lower selectivity relative to the neat polymer because they have increased mean free volume. Going beyond this ability to manipulate the mean free volume by grafting chains to a nanoparticle, the conceptual advance of the present work is our finding that GNPs are spatially heterogeneous transport media, with this free volume distribution being easily manipulated by the addition of free polymer. In particular, adding a small amount of appropriately chosen free polymer can increase the membrane gas selectivity by up to two orders of magnitude while only moderately reducing small gas permeability. Added short free chains, which are homogeneously distributed in the polymer layer of the GNP, reduce the permeability of all gases but yield no dramatic increases in selectivity. In contrast, free chains with length comparable to the grafts, which populate the interstitial pockets between GNPs, preferentially hinder the transport of the larger gas and thus result in large selectivity increases. This work thus establishes that we can favorably manipulate the selective gas transport properties of GNP membranes through the entropic effects associated with the addition of free chains.

MOF-Based Membranes for Gas Separations.

Metal-organic frameworks (MOFs) represent the largest known class of porous crystalline materials ever synthesized. Their narrow pore windows and nearly unlimited structural and chemical features have made these materials of significant interest for membrane-based gas separations. In this comprehensive review, we discuss opportunities and challenges related to the formation of pure MOF films and mixed-matrix membranes (MMMs). Common and emerging separation applications are identified, and membrane transport theory for MOFs is described and contextualized relative to the governing principles that describe transport in polymers. Additionally, cross-cutting research opportunities using advanced metrologies and computational techniques are reviewed. To quantify membrane performance, we introduce a simple membrane performance score that has been tabulated for all of the literature data compiled in this review. These data are reported on upper bound plots, revealing classes of MOF materials that consistently demonstrate promising separation performance. Recommendations are provided with the intent of identifying the most promising materials and directions for the field in terms of fundamental science and eventual deployment of MOF materials for commercial membrane-based gas separations.

Quantifying Patient Subpopulation Disparities in New Drugs and Biologics Approved Between 2007 and 2017.

BACKGROUND: Tufts CSDD conducted a study to quantify the magnitude of participant subgroup demographic disparities in industry-funded pivotal trials and establish baseline participant diversity measures. METHODS: Eleven years of data on pivotal trials of all novel drugs and biologics approved between 2007 and 2017 (n = 341 drugs and n = 757 pivotal trials) was compiled and analyzed. RESULTS: The availability of reported participant demographic subgroup data was poor-most notably participant ethnicity with 63% of pivotal trials supporting all approved treatments missing data. The availability of data on participant race and ethnicity did not improve between 2007 and 2017. Participants of Black or of African Descent were the subgroup most highly under-represented. Three times as many participants in this demographic subgroup should have been enrolled in pivotal trials to achieve representation as dictated by disease prevalence rates and population census figures. Although variation was observed between disease conditions, under-representation of Black/African Descent participants occurred in nearly all conditions. Participants from indigenous communities were also highly under-represented. Asian participants were highly over-represented in pivotal trials. Approximately 14% more Hispanic/Latinx participants should have been enrolled in clinical trials to achieve population-proportional representation. CONCLUSIONS: The results suggest that participant demographic disclosure practices are falling short and that insufficient diversity in clinical trials is limiting the value of guidance on medical treatment dosing and response. The study findings supplement the FDA's Drug Trial Snapshot Reports and offer insight into the magnitude of, and trends in, participant demographic subgroup disparities.

Mixed-Matrix Membranes Formed from Imide-Functionalized UiO-66-NH2 for Improved Interfacial Compatibility.

Mixed-matrix membranes (MMMs) formed by dispersing metal-organic framework (MOF) particles in polymers have attracted significant attention because these composite systems can potentially surpass the separation performance of pure polymers alone. However, performance improvements are often unrealized because of poor interfacial compatibility between the MOF and the polymer, which results in interfacial defects. From a practical perspective, strategies are needed to address these defects so that MMMs can be deployed in real-world separation processes. From a fundamental perspective, strategies are needed to reliably form defect-free MMMs so that transport models can be applied to estimate pure MOF property sets, thereby enabling the development of robust structure-property relationships. To address these interfacial challenges, we have developed a method to surface-functionalize a UiO-66-NH2 MOF with a nanoscopic shell of covalently tethered 4,4'-(hexafluoroisopropylidene)diphthalic anhydride-Durene oligomers. When combined with a high-molecular-weight polymer of identical chemical structure to that of the imide-functional MOF surface, defect-free MMMs with uniform particle dispersions can be formed. With this technique, both permeabilities and selectivities of select gases in the MMMs were improved at loadings ranging from 5 to 40 wt %. At a 40 wt % loading, CO2 permeability and CO2/CH4 selectivity were enhanced by 48 and 15%, respectively. Additionally, pure MOF permeabilities for H2, N2, O2, CH4, and CO2 were predicted by the Maxwell model.

Polymers with Side Chain Porosity for Ultrapermeable and Plasticization Resistant Materials for Gas Separations.

Polymer membranes with ultrahigh CO2 permeabilities and high selectivities are needed to address some of the critical separation challenges related to energy and the environment, especially in natural gas purification and postcombustion carbon capture. However, very few solution-processable, linear polymers are known today that access these types of characteristics, and all of the known structures achieve their separation performance through the design of rigid backbone chemistries that concomitantly increase chain stiffness and interchain spacing, thereby resulting in ultramicroporosity in solid-state chain-entangled films. Herein, the separation performance of a porous polymer obtained via ring-opening metathesis polymerization is reported, which possesses a flexible backbone with rigid, fluorinated side chains. This polymer exhibits ultrahigh CO2 permeability (>21 000 Barrer) and exceptional plasticization resistance (CO2 plasticization pressure > 51 bar). Compared to traditional polymers of intrinsic microporosity, the rate of physical aging is slower, especially for gases with small effective diameters (i.e., He, H2 , and O2 ). This structural design strategy, coupled with studies on fluorination, demonstrates a generalizable approach to create new polymers with flexible backbones and pore-forming side chains that have unexplored promise for small-molecule separations.

Mixed-Matrix Membranes Formed from Multi-Dimensional Metal-Organic Frameworks for Enhanced Gas Transport and Plasticization Resistance.

Mixed-matrix membranes (MMMs) formed by incorporating metal-organic frameworks (MOFs) into polymers have a general limitation in that the MOFs are typically formed into rather simple dimensionalities (such as 1D, 2D, or 3D). Each design approach has intrinsic-albeit independent-benefits, such as network percolation (1D), access to high-aspect ratios (2D), and ease of processability (3D). However, a design strategy is needed to combine multiple dimensionalities and, thereby, access the full range of transport and compositing benefits of these high-performance materials. Herein, a facile method to form multi-dimensional HKUST-1 nanoparticles is introduced by using a modulator to tune the MOF nucleation and growth mechanism. At 30 wt % multidimensional MOF loading, the MMM shows CO2 permeabilities of approximately 2500 Barrer, which represents a 2.5-fold increase compared to that of a pure polymer without a large loss of selectivity for CO2 /CH4 and CO2 /N2 . Additionally, almost no plasticization pressure response is observed for CO2 up to 750 psi, suggesting an unusual stability to high activity feeds.

Engineered Transport in Microporous Materials and Membranes for Clean Energy Technologies.

Many forward-looking clean-energy technologies hinge on the development of scalable and efficient membrane-based separations. Ongoing investment in the basic research of microporous materials is beginning to pay dividends in membrane technology maturation. Specifically, improvements in membrane selectivity, permeability, and durability are being leveraged for more efficient carbon capture, desalination, and energy storage, and the market adoption of membranes in those areas appears to be on the horizon. Herein, an overview of the microporous materials chemistry driving advanced membrane development, the clean-energy separations employing them, and the theoretical underpinnings tying membrane performance to membrane structure across multiple length scales is provided. The interplay of pore architecture and chemistry for a given set of analytes emerges as a critical design consideration dictating mass transport outcomes. Opportunities and outstanding challenges in the field are also discussed, including high-flux 2D molecular-sieving membranes, phase-change adsorbents as performance-enhancing components in composite membranes, and the need for quantitative metrologies for understanding mass transport in heterophasic materials and in micropores with unusual chemical interactions with analytes of interest.