Salient semantics.

Semantic features are components of concepts. In philosophy, there is a predominant focus on those features that are necessary (and jointly sufficient) for the application of a concept. Consequently, the method of cases has been the paradigm tool among philosophers, including experimental philosophers. However, whether a feature is salient is often far more important for cognitive processes like memory, categorization, recognition and even decision-making than whether it is necessary. The primary objective of this paper is to emphasize the significance of researching salient features of concepts. I thereby advocate the use of semantic feature production tasks, which not only enable researchers to determine whether a feature is salient, but also provide a complementary method for studying ordinary language use. I will discuss empirical data on three concepts, conspiracy theory, female/male professor, and life, to illustrate that semantic feature production tasks can help philosophers (a) identify those salient features that play a central role in our reasoning about and with concepts, (b) examine socially relevant stereotypes, and (c) investigate the structure of concepts.

Mutual entailment between causation and responsibility.

The standard view in philosophy is that responsibility entails causation. Most philosophers treat this entailment claim as an evident insight into the ordinary concepts of responsibility and causation. Further, it is taken to be equally obvious that the reversal of this claim does not hold: causation does not entail responsibility. In contrast, Sytsma and Livengood have put forward an account of the use of ordinary causal attributions (statements like "X caused Y") that contends that they are typically used interchangeably with responsibility attributions (statements like "X is responsible for Y"). Put in terms of the concepts at play in these attributions, this account suggests that the reversal of the entailment claim may also hold, and, a fortiori, there would be mutual entailment between the ordinary concepts of responsibility and causation. Using the cancellability test, we report the results of three pre-registered studies providing empirical evidence that causation and responsibility are mutually entailed by each other.

The varying rationality of weakness of the will: an empirical investigation and its challenges for a unified theory of rationality.

Weakness of the will remains a perplexing issue. Though philosophers have made substantial progress in homing in on what counts as a weak will, there is little agreement on whether weakness of the will is irrational, and if so, why. In this paper, we take an empirical approach towards the rationality of weakness of the will. After introducing the philosophical debate, we present the results of an empirical study that reveals that people take a "dual sensitivity", as we shall put it, towards assessing the rationality of weak-willed behavior. Put succinctly, intending X against your value judgements is assessed irrational; yet, in the same situation, intending X is assessed significantly less irrational if you judge X as something you ought to do. After discussing this result, we turn to the question of whether there is a plausible theory of rationality than can account for the dual sensitivity of the rationality assessments. We show that a success-based account can make sense of the dual sensitivity our empirical results reveal.

Mediating Passive Tumor Accumulation through Particle Size, Tumor Type, and Location.

As the enhanced permeation and retention (EPR) effect continues to be a controversial topic in nanomedicine, we sought to examine EPR as a function of nanoparticle size, tumor model, and tumor location, while also evaluating tumors for EPR mediating factors such as microvessel density, vascular permeability, lymphatics, stromal content, and tumor-associated immune cells. Tumor accumulation was evaluated for 55 × 60, 80 × 180, and 80 × 320 nm PRINT particles in four subcutaneous flank tumor models (SKOV3 human ovarian, 344SQ murine nonsmall cell lung, A549 human nonsmall cell lung, and A431 human epidermoid cancer). Each tumor model revealed specific particle accumulation trends with evident particle size dependence. Immuno-histochemistry staining revealed differences in tumor microvessel densities that correlated with overall tumor accumulation. Immunofluorescence images displayed size-mediated tumor penetration with signal from the larger particles concentrated close to the blood vessels, while signal from the smaller particle was observed throughout the tissue. Differences were also observed for the 55 × 60 nm particle tumor penetration across flank tumor models as a function of stromal content. The 55 × 60 nm particles were further evaluated in three orthotopic, metastatic tumor models (344SQ, A549, and SKOV3), revealing preferential accumulation in primary tumors and metastases over healthy tissue. Moreover, we observed higher tumor accumulation in the orthotopic lung cancer models than in the flank lung cancer models, whereas tumor accumulation was constant for both orthotopic and flank ovarian cancer models, further demonstrating the variability in the EPR effect as a function of tumor model and location.

USP Apparatus 4: a Valuable In Vitro Tool to Enable Formulation Development of Long-Acting Parenteral (LAP) Nanosuspension Formulations of Poorly Water-Soluble Compounds.

Long-acting or extended release parenteral dosage forms have attracted extensive attention due to their ability to maintain therapeutic drug concentrations over long periods of time and reduce administration frequency, thus improving patient compliance. It is essential to have an in vitro release (IVR) testing method that can be used to assure product quality during routine production as well as predict and understand the in vivo performance of a formulation. The purpose of this work was to develop a discriminatory in vitro release method to guide formulation and process development of long-acting parenteral (LAP) nanosuspension formulations composed of poorly water-soluble drugs (BCS class II). Injectable nanosuspension formulations were developed to serve as test articles for method development. Several different IVR methods were evaluated for their application to the formulation screening and process development including (1) USP apparatus 2, (2) dialysis and reverse dialysis sac, and (3) continuous flow-through cell (USP apparatus 4). Preliminary data shows the promising results to support the utilization of USP 4 over more widely accepted USP 2 and dialysis methods. A combination of more representative in vivo hydrodynamics and ease of maintaining sink conditions yields the USP 4 flow-through cell method a more suitable in vitro release method for nanosuspension-based LAP formulations of poorly water-soluble compounds, such as compounds A and B.

Making It Safe to Grow Old: A Financial Simulation Model for Launching MediCaring Communities for Frail Elderly Medicare Beneficiaries.

POLICY POINTS: At age 65, the average man and woman can respectively expect 1.5 years and 2.5 years of requiring daily help with "activities of daily living." Available services fail to match frail elders' needs, thereby routinely generating errors, unreliability, unwanted services, unmet needs, and high costs. The number of elderly Medicare beneficiaries likely to be frail will triple between 2000 and 2050. Low retirement savings, rising medical and long-term care costs, and declining family caregiver availability portend gaps in badly needed services. The financial simulation reported here for 4 diverse MediCaring Communities shows lower per capita costs. Program savings are substantial and can improve coverage and function of local supportive services within current overall Medicare spending levels. CONTEXT: The Altarum Institute Center for Elder Care and Advanced Illness has developed a reform model, MediCaring Communities, to improve services for frail elderly Medicare beneficiaries through longitudinal care planning, better-coordinated and more desirable medical and social services, and local monitoring and management of a community's quality and supply of services. This study uses financial simulation to determine whether communities could implement the model within current Medicare and Medicaid spending levels, an important consideration to enable development and broad implementation. METHODS: The financial simulation for MediCaring Communities uses 4 diverse communities chosen for adequate size, varying health care delivery systems, and ability to implement reforms and generate data rapidly: Akron, Ohio; Milwaukie, Oregon; northeastern Queens, New York; and Williamsburg, Virginia. For each community, leaders contributed baseline population and program effect estimates that reflected projections from reported research to build the model. FINDINGS: The simulation projected third-year savings between $269 and $537 per beneficiary per month and cumulative returns on investment between 75% and 165%. CONCLUSIONS: The MediCaring Communities financial simulation demonstrates that better care at lower cost for frail elderly Medicare beneficiaries is possible within current financing levels. Long-term success of the initiative will require reinvestment of Medicare savings to bolster nonmedical supportive services in the community. Successful implementation will necessitate waiving certain regulations and developing new infrastructure in pilot communities. This financial simulation methodology will help leadership in other communities to project fiscal performance. Since the MediCaring Communities model also achieves the Centers for Medicare and Medicaid Services' vision for care for frail elders (better care, healthier people, smarter spending) and since these reforms can proceed with limited waivers from Medicare, willing communities should explore implementation and share best practices about how to achieve fundamental service delivery changes that can meet the challenges of a much older population in the 21st century.

Targeted PRINT Hydrogels: The Role of Nanoparticle Size and Ligand Density on Cell Association, Biodistribution, and Tumor Accumulation.

In this Letter, we varied targeting ligand density of an EGFR binding affibody on the surface of two different hydrogel PRINT nanoparticles (80 nm × 320 and 55 nm × 60 nm) and monitored effects on target-cell association, off-target phagocytic uptake, biodistribution, and tumor accumulation. Interestingly, variations in ligand density only significantly altered in vitro internalization rates for the 80 nm × 320 nm particle. However, in vivo, both particle sizes experienced significant changes in biodistribution and pharmacokinetics as a function of ligand density. Overall, nanoparticle size and passive accumulation were the dominant factors eliciting tumor sequestration.

Calibration-quality cancer nanotherapeutics.

Nanoparticle properties such as size, shape, deformability, and surface chemistry all play a role in nanomedicine drug delivery in cancer. While many studies address the behavior of particle systems in a biological setting, revealing how these properties work together presents unique challenges on the nanoscale. "Calibration-quality" control over such properties is needed to draw adequate conclusions that are independent of parameter variability. Furthermore, active targeting and drug loading strategies introduce even greater complexities via their potential to alter particle pharmacokinetics. Ultimately, the investigation and optimization of particle properties should be carried out in the appropriate preclinical tumor model. In doing so, translational efficacy improves as clinical tumor properties increase. Looking forward, the field of nanomedicine will continue to have significant clinical impacts as the capabilities of nanoparticulate drug delivery are further enhanced.

Analysis of human innate immune responses to PRINT fabricated nanoparticles with cross validation using a humanized mouse model.

Ideal nanoparticle (NP)-based drug and vaccine delivery vectors should be free of inherent cytotoxic or immunostimulatory properties. Therefore, determining baseline immune responses to nanomaterials is of utmost importance when designing human therapeutics. We characterized the response of human immune cells to hydrogel NPs fabricated using Particle Replication in Non-wetting Templates (PRINT) technology. We found preferential NP uptake by primary CD14(+) monocytes, which was significantly reduced upon PEGylation of the NP surface. Multiplex cytokine analysis of NP treated primary human peripheral blood mononuclear cells suggests that PRINT based hydrogel NPs do not evoke significant inflammatory responses nor induce cytotoxicity or complement activation. We furthered these studies using an in vivo humanized mouse model and similarly found preferential NP uptake by human CD14(+) monocytes without systemic inflammatory cytokine responses. These studies suggest that PRINT hydrogel particles form a desirable platform for vaccine and drug delivery as they neither induce inflammation nor toxicity. From the clinical editor: The authors here fabricated hydrogel nanorods using the PRINT (Particle Replication In Nonwetting Templates) fabrication process. They tested the interaction of human immune cells with these particles and found no immunoreactivity. This finding would suggest that monodisperse PRINT particles of identical shape and size could serve a variety of clinical applications.

The ambiguity of "true" in English, German, and Chinese.

Through a series of empirical studies involving native speakers of English, German, and Chinese, this paper reveals that the predicate "true" is inherently ambiguous in the empirical domain. Truth statements such as "It is true that Tom is at the party" seem to be ambivalent between two readings. On the first reading, the statement means "Reality is such that Tom is at the party." On the second reading, the statement means "According to what X believes, Tom is at the party." While there appear to exist some cross-cultural differences in the interpretation of the statements, the overall findings robustly indicate that "true" has multiple meanings in the realm of empirical matters.

Evaluative Deflation, Social Expectations, and the Zone of Moral Indifference.

Acts that are considered undesirable standardly violate our expectations. In contrast, acts that count as morally desirable can either meet our expectations or exceed them. The zone in which an act can be morally desirable yet not exceed our expectations is what we call the zone of moral indifference, and it has so far been neglected. In this paper, we show that people can use positive terms in a deflated manner to refer to actions in the zone of moral indifference, whereas negative terms cannot be so interpreted.

Physiologically Based Biopharmaceutics Modeling for Gefapixant IR Formulation Development and Defining the Bioequivalence Dissolution Safe Space.

Gefapixant is a weakly basic drug which has been formulated as an immediate release tablet for oral administration. A physiologically based biopharmaceutics model (PBBM) was developed based on gefapixant physicochemical properties and clinical pharmacokinetics to aid formulation selection, bioequivalence safe space assessment and dissolution specification settings. In vitro dissolution profiles of different free base and citrate salt formulations were used as an input to the model. The model was validated against the results of independent studies, which included a bioequivalence and a relative bioavailability study, as well as a human ADME study, all meeting acceptance criteria of prediction errors ≤ 20% for both Cmax and AUC.  PBBM was also applied to evaluate gastric pH-mediated drug-drug-interaction potential with co-administration of a proton pump inhibitor (PPI), omeprazole. Model results showed good agreement with clinical data in which omeprazole lowered gefapixant exposure for the free base formulation but did not significantly alter gefapixant pharmacokinetics for the citrate based commercial drug product. An extended virtual dissolution bioequivalence safe space was established.  Gefapixant drug product batches are anticipated to be bioequivalent with the clinical reference batch when their dissolution is > 80% in 60 minutes. PBBM established a wide dissolution bioequivalence space as part of assuring product quality.

Effect of basket mesh size on the hydrodynamics of a partially filled (500 mL) USP rotating basket dissolution testing Apparatus 1.

The USP Rotating Basket Dissolution Testing Apparatus 1 is listed in the USP as one of the tools to assess dissolution of oral solid dosage forms. Baskets of different mesh sizes can be used to differentiate between dissolution profiles of different formulations. Here, we used Particle Image Velocimetry (PIV) to study the hydrodynamics of the USP Apparatus 1 using baskets with different mesh openings (10-, 20- and 40-mesh) revolving at 100 rpm, when the vessel was filled with 500 mL. The velocity profiles throughout the liquid were found to vary significantly using baskets of different mesh sizes, typically increasing with increased size of the opening of the basket mesh, especially for axial and radial velocities. This, in turn, resulted in a significantly different flow rate through the basket, which can be expected to significantly impact the dissolution rate of the drug product. A comparison between the results of this work with those of a previous study with a 900-mL fill volume (Sirasitthichoke et al., Intern. J. Pharmaceutics, 2021, 607: 120976), shows that although the hydrodynamics in the USP Apparatus 1 changed with fill level in the vessel, the flow rate through the basket was not significantly affected. This implies that tablets dissolving in the two systems would experience similar tablet-liquid medium mass transfer coefficients, and therefore similar initial dissolution rates, but different dissolution profiles because of the difference in volume.

PEGylated PRINT nanoparticles: the impact of PEG density on protein binding, macrophage association, biodistribution, and pharmacokinetics.

In this account, we varied PEGylation density on the surface of hydrogel PRINT nanoparticles and systematically observed the effects on protein adsorption, macrophage uptake, and circulation time. Interestingly, the density of PEGylation necessary to promote a long-circulating particle was dramatically less than what has been previously reported. Overall, our methodology provides a rapid screening technique to predict particle behavior in vivo and our results deliver further insight to what PEG density is necessary to facilitate long-circulation.

Influence of basket mesh size on the hydrodynamics in the USP rotating basket dissolution testing Apparatus 1.

The USP Apparatus 1 (rotating basket), typically used to assess drug product reproducibility and evaluate oral solid dosage forms performance, consists of a cylindrical glass vessel with a hemispherical bottom and a wire basket rotating at constant speed. Baskets with different wire openings can be used in alternative to the standard mesh opening (40-mesh) in order to discriminate between drug formulations during early stage of drug product development. Any changes introduced by different basket geometries can potentially and significantly impact the system hydrodynamics and cause variability of results, thus affecting product quality. In this work, Particle Image Velocimetry (PIV) was used to experimentally quantify the velocity distribution in the USP rotating basket Apparatus 1 using baskets of different mesh sizes (10-, 20-, and 40-mesh size) under the typical operating conditions described in dissolution testing procedures. Similar flow patterns were observed in all cases. However, the radial and axial velocities in the USP Apparatus 1 generally increased with increasingly larger openings of the basket mesh. Increasing the basket agitation speed also resulted in an overall increase in the velocities, especially below in the innermost core region below the basket, where drug fragments typically reside. More importantly, the flow entering and leaving the baskets was quantified from the velocity profiles in the immediate vicinity of the baskets. It was found that the flow increased significantly with increasingly larger mesh openings, which can, in turn, promote faster dissolution of the oral solid dosage forms, thus affecting drug dissolution profiles. Hence, the selection of the basket mesh size must be carefully considered during drug product development.

Incidence, Risk Factors and Impact on Long-Term Outcome of Postoperative Delirium After Transcatheter Aortic Valve Replacement.

Background: The aim of the present study was to analyze incidence, risk factors, and association with long-term outcome of postoperative delirium (POD) after transcatheter aortic valve replacement (TAVR). Methods: Six hundred and sixty one consecutive patients undergoing TAVR were prospectively enrolled from January 2016 to December 2017. POD was assessed regularly during ICU-stay using the CAM-ICU test. Results: The incidence of POD was 10.0% (n = 66). Patients developing POD were predominantly male (65%), had higher EuroSCORE II (5.4% vs. 3.9%; P = 0.041) and were more often considered frail (70% vs. 26%; P < 0.001). POD was associated with more peri-procedural complications including vascular complications (19.7 vs. 9.4; P = 0.017), bleeding (12.1 vs. 5.4%; P = 0.0495); stroke (4.5 vs. 0.7%; P = 0.025), respiratory failure requiring ventilation (16.7% vs. 1.8%; P < 0.001), and pneumonia (34.8% vs. 7.1%; P < 0.001). Consequently, patients with POD had significantly longer ICU- (7.9 vs. 3.2 days P < 0.001) and hospital-stay (14.9 vs. 9.0 days; P < 0.001), and higher in-hospital mortality (6.1 vs. 2.1%; P = 0.017). Logistic regression analysis identified male sex (odds ratio (OR) 2.2 [95% confidence interval (CI) 1.2-4.0); P = 0.012], atrial fibrillation [OR 3.0 (CI 1.6-5.6); P < 0.001], frailty [OR 4.3 (CI 2.4-7.9); P < 0.001], pneumonia [OR 4.4 (CI 2.3-8.7); P < 0.001], stroke [OR 7.0 (CI 1.2-41.6); P = 0.031], vascular complication [OR 2.9 (CI 1.3-6.3); P = 0.007], and general anesthesia [OR 2.0 (CI 1.0-3.7); P = 0.039] as independent predictors of POD. On Cox proportional hazard analysis POD emerged as a significant predictor of 2-year mortality [HR 1.89 (CI 1.06-3.36); P = 0.030]. Conclusion: POD is a frequent finding after TAVR and is significantly associated with reduced 2-year survival. Predictors of delirium include not only peri-procedural parameters like stroke, pneumonia, vascular complications and general anesthesia but also baseline characteristics as male sex, atrial fibrillation and frailty.

Biowaiver Applications in Support of a Polymorph During Late-Stage Clinical Development of Verubecestat-Current Challenges and Future Opportunities for Global Regulatory Alignment.

Dissolution experiments to support an active pharmaceutical ingredient (API) form change in Verubecestat immediate release tablets were performed following current regulatory guidance published by health authorities in Canada, Australia, Japan, the EU, and the USA. Verubecestat API meets the requirements of a Biopharmaceutics Classification System class 1 compound and tablets are very  rapidly dissolving in aqueous dissolution media. While the in vitro data were reviewed favorably by these agencies, the divergence in regulatory requirements led to unnecessary work and highlights several issues companies operating globally face to justify product changes that have very little impact on quality. The data presented in this manuscript provide a compelling case for adjustments to the current draft ICH M9 guidance which provides recommendations for biowaiver applications. Specifically, this manuscript contains recommendations with respect to API attributes, selection of dissolution media and apparatus, and methods to assess dissolution similarity if needed, which should be considered for inclusion in a science- and risk-based global guidance document to benefit patients, regulators, and the pharmaceutical industry.

Dual Character Concepts in Social Cognition: Commitments and the Normative Dimension of Conceptual Representation.

The concepts expressed by social role terms such as artist and scientist are unique in that they seem to allow two independent criteria for categorization, one of which is inherently normative (Knobe, Prasada, & Newman, 2013). This study presents and tests an account of the content and structure of the normative dimension of these "dual character concepts." Experiment 1 suggests that the normative dimension of a social role concept represents the commitment to fulfill the idealized basic function associated with the role. Background information can affect which basic function is associated with each social role. However, Experiment 2 indicates that the normative dimension always represents the relevant commitment as an end in itself. We argue that social role concepts represent the commitments to basic functions because that information is crucial to predict the future social roles and role-dependent behavior of others.

Evaluation of drug loading, pharmacokinetic behavior, and toxicity of a cisplatin-containing hydrogel nanoparticle.

Cisplatin is a cytotoxic drug used as a first-line therapy for a wide variety of cancers. However, significant renal and neurological toxicities limit its clinical use. It has been documented that drug toxicities can be mitigated through nanoparticle formulation, while simultaneously increasing tumor accumulation through the enhanced permeation and retention effect. Circulation persistence is a key characteristic for exploiting this effect, and to that end we have developed long-circulating, PEGylated, polymeric hydrogels using the Particle Replication In Non-wetting Templates (PRINT®) platform and complexed cisplatin into the particles (PRINT-Platin). Sustained release was demonstrated, and drug loading correlated to surface PEG density. A PEG Mushroom conformation showed the best compromise between particle pharmacokinetic (PK) parameters and drug loading (16wt.%). While the PK profile of PEG Brush was superior, the loading was poor (2wt.%). Conversely, the drug loading in non-PEGylated particles was better (20wt.%), but the PK was not desirable. We also showed comparable cytotoxicity to cisplatin in several cancer cell lines (non-small cell lung, A549; ovarian, SKOV-3; breast, MDA-MB-468) and a higher MTD in mice (10mg/kg versus 5mg/kg). The pharmacokinetic profiles of drug in plasma, tumor, and kidney indicate improved exposure in the blood and tumor accumulation, with concurrent renal protection, when cisplatin was formulated in a nanoparticle. PK parameters were markedly improved: a 16.4-times higher area-under-the-curve (AUC), a reduction in clearance (CL) by a factor of 11.2, and a 4.20-times increase in the volume of distribution (Vd). Additionally, non-small cell lung and ovarian tumor AUC was at least twice that of cisplatin in both models. These findings suggest the potential for PRINT-Platin to improve efficacy and reduce toxicity compared to current cisplatin therapies.

The good, the bad, and the timely: how temporal order and moral judgment influence causal selection.

Causal selection is the cognitive process through which one or more elements in a complex causal structure are singled out as actual causes of a certain effect. In this paper, we report on an experiment in which we investigated the role of moral and temporal factors in causal selection. Our results are as follows. First, when presented with a temporal chain in which two human agents perform the same action one after the other, subjects tend to judge the later agent to be the actual cause. Second, the impact of temporal location on causal selection is almost canceled out if the later agent did not violate a norm while the former did. We argue that this is due to the impact that judgments of norm violation have on causal selection-even if the violated norm has nothing to do with the obtaining effect. Third, moral judgments about the effect influence causal selection even in the case in which agents could not have foreseen the effect and did not intend to bring it about. We discuss our findings in connection to recent theories of the role of moral judgment in causal reasoning, on the one hand, and to probabilistic models of temporal location, on the other.