A Prodrug Strategy to Reposition Atovaquone as a Long-Acting Injectable for Malaria Chemoprotection.

Recent malaria drug discovery approaches have been extensively focused on the development of oral, smallmolecule inhibitors for disease treatment whereas parenteral routes of administration have been avoided due to limitations in deploying a shelf-stable injectable even though it could be dosed less frequently. However, an updated target candidate profile from Medicines for Malaria Venture (MMV) and stakeholders have advocated for long-acting injectable chemopreventive agents as an important interventive tool to improve malaria prevention. Here, we present strategies for the development of a long-acting, intramuscular, injectable atovaquone prophylactic therapy. We have generated three prodrug approaches that are contrasted by their differential physiochemical properties and pharmacokinetic profiles: mCBK068, a docosahexaenoic acid ester of atovaquone formulated in sesame oil, mCKX352, a heptanoic acid ester of atovaquone formulated as a solution in sesame oil, and mCBE161, an acetic acid ester of atovaquone formulated as an aqueous suspension. As a result, from a single 20 mg/kg intramuscular injection, mCKX352 and mCBE161 maintain blood plasma exposure of atovaquone above the minimal efficacious concentration for >70 days and >30 days, respectively, in cynomolgus monkeys. The differences in plasma exposure are reflective of the prodrug strategy, which imparts altered chemical properties that ultimately influence aqueous solubility and depot release kinetics. On the strength of the pharmacokinetic and safety profiles, mCBE161 is being advanced as a first-in-class clinical candidate for first-in-human trials.

Comparison of Bordetella species identification among differing rt-PCR assays in the United States.

In the United States, the general laboratory method for diagnosing pertussis, caused by Bordetella pertussis, is real-time PCR (rt-PCR) targeting insertion sequence 481 (IS481). Other Bordetella species (parapertussis, holmesii, and bronchiseptica) can also cause a pertussis-like syndrome, and some commercial laboratory assays include the insertion sequence 1001 (pIS1001) that can detect B. parapertussis/B. bronchiseptica (BppBb). Because IS481 exists in B. pertussis and B. holmesii, current commercial assays cannot differentiate these two species. We used a multiplex rt-PCR assay containing species-specific targets to Bordetella to evaluate clinical specimens detected as B. pertussis/B. holmesii (BpBh) or BppBb by commercial laboratories. A sample of 3,984 clinical specimens positive for IS481 or pIS1001 from two commercial laboratories during 2012-2019 were re-tested at CDC. Agreement of Bordetella species between the CDC and commercial laboratory assays, and the proportion of commercial laboratory specimens that were non-B. pertussis by CDC's assay was assessed. Overall agreement in Bordetella species detection and identification between the CDC and commercial lab assays was 85%. Agreement for identifying B. pertussis was 87% for 3,663 BpBh specimens and 98% for identifying B. parapertussis in 310 BppBb specimens. CDC's assay detected B. holmesii in 55/3,984 (1.4%) specimens. Most discrepant results (410/490, 82%) were BpBh specimens interpreted as indeterminate B. pertussis at CDC. We found a small portion of B. holmesii in a sample of IS481-positive clinical specimens originally identified by commercial laboratory rt-PCR assays, suggesting that commercial PCR assays are a reliable diagnostic tool for correctly identifying Bordetella species in most patients with suspected pertussis. IMPORTANCE: When testing specimens collected from patients with suspected pertussis, large-scale commercial laboratories in the United States employ an IS481-based assay that cannot differentiate between Bordetella pertussis and Bordetella holmseii. The level of B. holmesii causing pertussis-like illness in the United States is not well-understood given that only B. pertussis is nationally notifiable. After re-testing with a multiplex, species-specific rt-PCR assay, our data show low levels of B. holmesii identified in a sample of IS481-positive clinical specimens originally identified by commercial laboratory rt-PCR assays. These results reinforce the validity of large-scale commercial rt-PCR testing as a reliable diagnostic tool for pertussis in the United States.

Identification of mCMQ069, a novel antimalarial with potential for a single-dose cure and/or 28-day chemoprevention.

In efforts towards eliminating malaria, a discovery program was initiated to identify a novel antimalarial using KAF156 as a starting point. Following the most recent TCP/TPP guidelines, we have identified mCMQ069 with a predicted single oral dose for treatment (∼40-106 mg) and one-month chemoprevention (∼96-216 mg). We have improved unbound MPC and predicted human clearance by 18-fold and 10-fold respectively when compared to KAF156.

Advancing Synthetic Hydrogels through Nature-Inspired Materials Chemistry.

Synthetic extracellular matrix (ECM) mimics that can recapitulate the complex biochemical and mechanical nature of native tissues are needed for advanced models of development and disease. Biomedical research has heavily relied on the use of animal-derived biomaterials, which is now impeding their translational potential and convoluting the biological insights gleaned from in vitro tissue models. Natural hydrogels have long served as a convenient and effective cell culture tool, but advances in materials chemistry and fabrication techniques now present promising new avenues for creating xenogenic-free ECM substitutes appropriate for organotypic models and microphysiological systems. However, significant challenges remain in creating synthetic matrices that can approximate the structural sophistication, biochemical complexity, and dynamic functionality of native tissues. This review summarizes key properties of the native ECM, and discusses recent approaches used to systematically decouple and tune these properties in synthetic matrices. The importance of dynamic ECM mechanics, such as viscoelasticity and matrix plasticity, is also discussed, particularly within the context of organoid and engineered tissue matrices. Emerging design strategies to mimic these dynamic mechanical properties are reviewed, such as multi-network hydrogels, supramolecular chemistry, and hydrogels assembled from biological monomers.

Entropy Drives Accelerated Ion Diffusion upon Carbon Dioxide Expansion of Electrolytes.

Carbon dioxide-expanded liquids, organic solvents with high concentrations of soluble carbon dioxide (CO2) at mild pressures, have gained attention as green catalytic media due to their improved properties over traditional solvents. More recently, carbon dioxide-expanded electrolytes (CXEs) have demonstrated improved reaction rates in the electrochemical reduction of CO2, by increasing the rate of delivery of CO2 to the electrode while maintaining facile charge transport. However, recent studies indicate that the limiting behavior of CXEs at higher CO2 pressures is a decline in solution conductivity due to reduced polarity, leading to poorer charge screening and greater ion pairing. In this article, we employ molecular dynamics simulations to investigate the energetic driving forces behind the diffusive properties of an acetonitrile and tetrapropylammonium hexafluorophosphate (TPrAPF6) CXE with increasing CO2 concentration. Our results indicate that entropy drives solvent and electrolyte diffusion with increasing CO2 pressure. The activation energy of ion diffusion increases with higher concentrations of CO2, indicating that increasing the temperature may improve solution conductivity in these systems. This trend in the activation energies is traced to stronger cation-anion Coulombic interactions due to weaker solvent screening at high CO2 concentrations, suggesting that the choice of ion may provide a route to diminish this effect.

Targeted mutational profiling of Epstein Barr virus-positive mucocutaneous ulcer: Implications for differential diagnosis with EBV-positive diffuse large B-cell lymphoma.

Epstein Barr Virus-positive mucocutaneous ulcer (EBVMCU) can be difficult to distinguish from EBV-positive diffuse large B cell lymphoma (DLBCL). We used targeted next-generation sequencing (NGS) to explore genetic alterations in EBVMCU to aid in this diagnostic challenge. Ten cases of EBVMCU were evaluated by a targeted NGS panel of 164 genes. Targeted NGS identified 18 variants in 15 genes in eight cases of EBVMCU. Loss of function TET2 variants were most frequently identified (3 of 10 cases, 30 %). One TET2 variant occurred at low variant allele frequency (VAF) of 3 %, which may be suggestive of clonal hematopoiesis of indeterminate potential. One case harbored a loss of function DNMT3A variant at low VAF. Two cases demonstrated missense variants in the IRF8 gene. Both variants occurred at a VAF close to 50 % and with an estimated high burden of disease (75 %). Two cases of mucosal gastrointestinal involvement had no reportable variants. Mutational profiling of EBVMCU identified TET2 loss of function variants at an elevated frequency in our cohort; however, the findings are not specific and its clinical significance cannot be completely elucidated. Further studies are needed to confirm the findings in an independent and larger cohort of EBVMCU, to determine the cell of origin of the variants, and to further assess their significance in the pathogenesis of this disorder.

North American pitseed goosefoot (Chenopodium berlandieri) is a genetic resource to improve Andean quinoa (C. quinoa).

Pitseed goosefoot (Chenopodium berlandieri) is a free-living North American member of an allotetraploid complex that includes the Andean pseudocereal quinoa (C. quinoa). Like quinoa, pitseed goosefoot was domesticated, possibly independently, in eastern North America (subsp. jonesianum) and Mesoamerica (subsp. nuttaliae). To test the utility of C. berlandieri as a resource for quinoa breeding, we produced the whole-genome DNA sequence of PI 433,231, a huauzontle from Puebla, México. The 1.295 Gb genome was assembled into 18 pseudomolecules and annotated using RNAseq data from multiple tissues. Alignment with the v.2.0 genome of Chilean-origin C. quinoa cv. 'QQ74' revealed several inversions and a 4A-6B reciprocal translocation. Despite these rearrangements, some quinoa x pitseed goosefoot crosses produce highly fertile hybrids with faithful recombination, as evidenced by a high-density SNP linkage map constructed from a Bolivian quinoa 'Real-1' × BYU 937 (Texas coastal pitseed goosefoot) F2 population. Recombination in that cross was comparable to a 'Real-1' × BYU 1101 (Argentine C. hircinum) F2 population. Furthermore, SNP-based phylogenetic and population structure analyses of 90 accessions supported the hypothesis of multiple independent domestications and descent from a common 4 × ancestor, with a likely North American Center of Origin.

Rescuing Photoreceptors in RPE Dysfunction-Driven Retinal Degeneration: The Role of Small Extracellular Vesicles Secreted from Retinal Pigment Epithelium.

Dysfunction of the retinal pigment epithelium (RPE) is a common shared pathology in major degenerative retinal diseases despite variations in the primary etiologies of each disease. Due to their demanding and indispensable functional roles throughout the lifetime, RPE cells are vulnerable to genetic predisposition, external stress, and aging processes. Building upon recent advancements in stem cell technology for differentiating healthy RPE cells and recognizing the significant roles of small extracellular vesicles (sEV) in cellular paracrine and autocrine actions, we investigated the hypothesis that the RPE-secreted sEV alone can restore essential RPE functions and rescue photoreceptors in RPE dysfunction-driven retinal degeneration. Our findings support the rationale for developing intravitreal treatment of sEV. We demonstrate that intravitreally delivered sEV effectively penetrate the full thickness of the retina. Xenogenic intraocular administration of human-derived EVs did not induce acute immune reactions in rodents. sEV derived from human embryonic stem cell (hESC)-derived fully differentiated RPE cells, but not sEV-depleted conditioned cell culture media (CCM minus sEV), rescued photoreceptors and their function in a Royal College of Surgeons (RCS) rat model. This model is characterized by photoreceptor death and retinal degeneration resulting from a mutation in the MerTK gene in RPE cells. From the bulk RNA sequencing study, we identified 447 differently expressed genes in the retina after hESC-RPE-sEV treatment compared with the untreated control. Furthermore, 394 out of 447 genes (88%) showed a reversal in expression toward the healthy state in Long-Evans (LE) rats after treatment compared to the diseased state. Particularly, detrimental alterations in gene expression in RCS rats, including essential RPE functions such as phototransduction, vitamin A metabolism, and lipid metabolism were partially reversed. Defective photoreceptor outer segment engulfment due to intrinsic MerTK mutation was partially ameliorated. These findings suggest that RPE-secreted sEV may play a functional role similar to that of RPE cells. Our study justifies further exploration to fully unlock future therapeutic interventions with sEV in a broad array of degenerative retinal diseases.

C(sp3)-H (N-Phenyltetrazole)thiolation as an Enabling Tool for Molecular Diversification.

Methods enabling the broad diversification of C(sp3)-H bonds from a common intermediate are especially valuable in chemical synthesis. Herein, we report a site-selective (N-phenyltetrazole)thiolation of aliphatic and (hetero)benzylic C(sp3)-H bonds using a commercially available disulfide to access N-phenyltetrazole thioethers. The thioether products are readily elaborated in diverse fragment couplings for C-C, C-O, or C-N construction. The C-H functionalization proceeds via a radical-chain pathway involving hydrogen atom transfer by the electron-poor N-phenyltetrazolethiyl radical. Hexafluoroisopropanol was found to be essential to reactions involving aliphatic C(sp3)-H thiolation, with computational analysis consistent with dual hydrogen bonding of the N-phenyltetrazolethiyl radical imparting increased radical electrophilicity to facilitate the hydrogen atom transfer. Substrate is limiting reagent in all cases, and the reaction displays an exceptional functional group tolerance well suited to applications in late-stage diversification.

Repurposing mebendazole against triple-negative breast cancer CNS metastasis.

PURPOSE: Triple-negative breast cancer (TNBC) often metastasizes to the central nervous system (CNS) and has the highest propensity among breast cancer subtypes to develop leptomeningeal disease (LMD). LMD is a spread of cancer into leptomeningeal space that speeds up the disease progression and severely aggravates the prognosis. LMD has limited treatment options. We sought to test whether the common anti-helminthic drug mebendazole (MBZ) may be effective against murine TNBC LMD. METHODS: A small-molecule screen involving TNBC cell lines identified benzimidazoles as potential therapeutic agents for further study. In vitro migration assays were used to evaluate cell migration capacity and the effect of MBZ. For in vivo testing, CNS metastasis was introduced into BALB/c athymic nude mice through internal carotid artery injections of brain-tropic MDA-MB-231-BR or MCF7-BR cells. Tumor growth and spread was monitored by bioluminescence imaging and immunohistochemistry. MBZ was given orally at 50 and 100 mg/kg doses. MBZ bioavailability was assayed by mass spectrometry. RESULTS: Bioinformatic analysis and migration assays revealed higher migratory capacity of TNBC compared to other breast cancer subtypes. MBZ effectively slowed down migration of TNBC cell line MDA-MB-231 and its brain tropic derivative MDA-MB-231-BR. In animal studies, MBZ reduced leptomeningeal spread, and extended survival in brain metastasis model produced by MDA-MB-231-BR cells. MBZ did not have an effect in the non-migratory MCF7-BR model. CONCLUSIONS: We demonstrated that MBZ is a safe and effective oral agent in an animal model of TNBC CNS metastasis. Our findings are concordant with previous efforts involving MBZ and CNS pathology and support the drug's potential utility to slow down leptomeningeal spread.

German and Italian validation of the Dyadic Coping Inventory-Sexual Minority Stress (DCI-SMS) scale.

Lesbian, gay, bisexual, and transgender individuals (hereafter people with minoritized sexual orientation and/or gender identities) have limited legal rights and access to resources because of their marginalized status in society. These limitations are associated with notable health disparities and increase experiences of minority stress. For those in a romantic relationship, being able to communicate and cope with one's partner-dyadic coping-can help buffer stress' deleterious effects on well-being. Given the promise of understanding how dyadic coping can mitigate experiences of sexual minority stress, the Dyadic Coping Inventory-Sexual Minority Stress (DCI-SMS) was recently created and validated with those living in the United States to assess how partners cope with sexual minority stress. Answering a global call to expand psychological science beyond a U.S. centric perspective, the purpose of this study was to validate the DCI-SMS in German and Italian using samples from Austria, Germany, Switzerland, and Italy, respectively. Confirmatory factor analysis results, along with tests of convergent and discriminant validity, and measurement invariance, suggest that the DCI-SMS is a valid measure of stress communication and dyadic coping behaviors for those in a same-gender relationship in the countries sampled. Important future directions include examining its efficacy in other countries, such as those with more adverse sociopolitical climates for people with minoritized sexual orientation and/or gender identities in a same-gender relationship. Limitations and future directions for research and clinical practice are presented. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Unveiling the Strong Black Woman Schema-Evolution and Impact: A Systematic Review.

The Strong Black Woman (SBW) schema is described as a statue of unrelenting strength, resilience, and self-sufficiency, serving as a shield of protection and cultural adaptation to suppress and control manifestations of racial and gender oppression. Stemming from superwoman syndrome, a conceptual model exploring the multifactorial roles women hold and their impact, the SBW extends beyond gender roles to the sociopolitical context of the Black woman's lived experience. Endorsement of the SBW posits risk for health disparities including stress, anxiety, depression, and obesity. This review was conducted to explore the SBW schema and experiences of Black women who endorse it, to delineate how Black women describe themselves in relation to the SBW persona, and to inform further inquiry, nursing practice, and clinical approaches to improving health outcomes of this population. A systematic review of qualitative studies was conducted with a literature search from CINAHL, APA PsycINFO, MEDLINE, PubMed, and SocINDEX databases yielding seven relevant papers for this analysis. Studies using the superwoman schema and the SBW schema with participants who identified as Black women were included in the review. Consistent with the SBW phenomenon, many participants described examples and consequences of being an SBW. While most women identified with SBW, not all endorsed the persona entirely, challenging its ideal and reinforcing positive self-care. Themes include (a) Strength by nature, not choice, (b) Suppressed emotion, (c) Success over everything, and (d) Prioritizing others over self. Additional emerging themes are also included. Black women increasingly recognize the negative impacts of the SBW schema, pinpointing how their internal feelings manifest in their external world. The conceptual framework itself is an anomaly, incongruently impacting both the mental and physical health of Black women, further contributing to the long-term health and sociopolitical disparities that Black women experience. Simply acknowledging and understanding these experiences by healthcare practitioners are not enough to prevent or eliminate the risks involved with the endorsement of the SBW schema but rather intentionally addressing these as a contributing social determinant of health that predisposes them to long-term chronic conditions.

Select EZH2 inhibitors enhance viral mimicry effects of DNMT inhibition through a mechanism involving NFAT:AP-1 signaling.

DNA methyltransferase inhibitor (DNMTi) efficacy in solid tumors is limited. Colon cancer cells exposed to DNMTi accumulate lysine-27 trimethylation on histone H3 (H3K27me3). We propose this Enhancer of Zeste Homolog 2 (EZH2)-dependent repressive modification limits DNMTi efficacy. Here, we show that low-dose DNMTi treatment sensitizes colon cancer cells to select EZH2 inhibitors (EZH2is). Integrative epigenomic analysis reveals that DNMTi-induced H3K27me3 accumulates at genomic regions poised with EZH2. Notably, combined EZH2i and DNMTi alters the epigenomic landscape to transcriptionally up-regulate the calcium-induced nuclear factor of activated T cells (NFAT):activating protein 1 (AP-1) signaling pathway. Blocking this pathway limits transcriptional activating effects of these drugs, including transposable element and innate immune response gene expression involved in viral defense. Analysis of primary human colon cancer specimens reveals positive correlations between DNMTi-, innate immune response-, and calcium signaling-associated transcription profiles. Collectively, we show that compensatory EZH2 activity limits DNMTi efficacy in colon cancer and link NFAT:AP-1 signaling to epigenetic therapy-induced viral mimicry.

Epstein-Barr virus latency patterns in polymorphic lymphoproliferative disorders and lymphomas in immunodeficiency settings: Diagnostic implications.

Epstein-Barr virus (EBV) is responsible for many B cell lymphoproliferative disorders (LPD) spanning subclinical infection to immunodeficiency-related neoplasms. EBV establishes a latent infection in the host B cell as defined histologically by the expression of EBV latent membrane proteins and nuclear antigens. Herein, we characterize the latency patterns of immunodeficiency-related neoplasms including post-transplant lymphoproliferative disorders (PTLD) and therapy-related LPD (formerly iatrogenic) with latent membrane protein-1 (LMP-1) and EBV nuclear antigen-2 (EBNA-2) immunohistochemistry. The latency pattern was correlated with immunodeficiency and dysregulation (IDD) status and time from transplant procedure. 38 cases of EBV+ PTLD in comparison to 27 cases of classic Hodgkin lymphoma (CHL) and diffuse large B cell lymphoma (DLBCL) arising in either the therapy-related immunodeficiency setting (n = 12) or without an identified immunodeficiency (n = 15) were evaluated for EBV-encoded small RNAs by in situ hybridization (EBER-ISH) and for LMP-1 and EBNA-2 by immunohistochemistry. A full spectrum of EBV latency patterns was observed across PTLD in contrast to CHL and DLBCL arising in the therapy-related immunodeficiency setting. Polymorphic-PTLD (12 of 16 cases, 75 %) and DLBCL-PTLD (9 of 11 cases, 82 %) showed the greatest proportion of cases with latency III pattern. Whereas, EBV+ CHL in an immunocompetent patient showed exclusively latency II pattern (13 of 13 cases, 100 %). The majority of EBV+ PTLD occurred by three years of transplant procedure date and were enriched for latency III pattern (21 of 22 cases, 95 %). Immunohistochemical identification of EBV latency by LMP-1 and EBNA-2 can help classify PTLD in comparison to other EBV+ B cell LPD and lymphomas arising in therapy-related immunodeficiency and non-immunodeficiency settings.

The Sexual Encounters Questionnaire: A gender-inclusive survey of sexual victimization across the lifespan.

OBJECTIVE: Despite sexual victimization posing a serious social problem worldwide, inconsistencies in the conceptualization, definition, and measurement of sexual violence mean that many victims are not included in surveys designed to quantify the nature of this problem. The present studies developed, piloted, and finalized a novel survey of victimization, the sexual encounters questionnaire (SEQ), a robust and extensive tool that screens for a range of sexual violation scenarios that can be perpetrated against a victim of any gender and age. METHOD: Study 1 piloted the original version of the SEQ among 458 students while Study 2 examined the psychometric properties of the SEQ in a sample of 150 students. RESULTS: Study 1 found an overall victimization rate of 76.9%, with 59.8% of men and 80.5% of women being identified as victims. The prevalence and severity of victimization were higher among women than men. Twelve-month prevalence rates ranged from 2.2% to 23.4% depending on the type of violation surveyed with an overall 12-month prevalence of 34.9%. Study 2 found convergent validity with other measures of sexual victimization, and discriminant validity with participants' political orientation and a fear of intimacy measure. CONCLUSION: The SEQ, with more sensitivity to detect sexual victimization, showed high levels of victimization in students. These results suggest the usefulness of the SEQ as a gender-inclusive screening tool for sexual victimization across the lifespan. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Isolation and Characterization of Extracellular Vesicles Through Orthogonal Approaches for the Development of Intraocular EV Therapy.

Purpose: Isolating extracellular vesicles (EVs) with high yield, replicable purity, and characterization remains a bottleneck in the development of EV therapeutics. To address these challenges, the current study aims to establish the necessary framework for preclinical and clinical studies in the development of stem cell-derived intraocular EV therapeutics. Methods: Small EVs (sEVs) were separated from the conditioned cell culture medium (CCM) of the human embryogenic stem cell-derived fully polarized retinal pigment epithelium (hESC-RPE-sEV) by a commercially available microfluidic tangential flow filtration (TFF) device ExoDisc (ED) or differential ultracentrifugation (dUC). The scaling and concentration capabilities and purity of recovered sEVs were assessed. Size, number, and surface markers of sEVs were determined by orthogonal approaches using multiple devices. Results: ED yielded higher numbers of sEVs, ranging from three to eight times higher depending on the measurement device, compared to dUC using the same 5 mL of CCM input. Within the same setting, the purity of ED-recovered hESC-RPE-sEVs was higher than that for dUC-recovered sEVs. ED yielded a higher concentration of particles, which is strongly correlated with the input volume, up to 10 mL (r = 0.98, P = 0.016). Meanwhile, comprehensive characterization profiles of EV surface markers between ED- and dUC-recovered hESC-RPE-sEVs were compatible. Conclusions: Our study supports TFF as a valuable strategy for separating sEVs for the development of intraocular EV therapeutics. However, there is a growing need for diverse devices to optimize TFF for use in EV preparation. Using orthogonal approaches in EV characterization remains ideal for reliably characterizing heterogeneous EV.

Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Warhead.

There remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by an increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target due to its homology within the coronaviral family, and lack thereof toward human proteases. In this disclosure, we outline the advent of a novel SARS-CoV-2 3CLpro inhibitor, CMX990, bearing an unprecedented trifluoromethoxymethyl ketone warhead. Compared with the marketed drug nirmatrelvir (combination with ritonavir = Paxlovid), CMX990 has distinctly differentiated potency (∼5× more potent in primary cells) and human in vitro clearance (>4× better microsomal clearance and >10× better hepatocyte clearance), with good in vitro-to-in vivo correlation. Based on its compelling preclinical profile and projected once or twice a day dosing supporting unboosted oral therapy in humans, CMX990 advanced to a Phase 1 clinical trial as an oral drug candidate for SARS-CoV-2.

Nudging During Pediatric Intensive Care Conferences With Family Members: Retrospective Analysis of Transcripts From a Single-Center, 2015-2019.

OBJECTIVES: Nudging, a behavioral economics concept, subtly influences decision-making without coercion or limiting choice. Despite its frequent use, the specific application of nudging techniques by clinicians in shared decision-making (SDM) is understudied. Our aim was to analyze clinicians' use of nudging in a curated dataset of family care conferences in the PICU. DESIGN: Between 2019 and 2020, we retrospectively studied and coded 70 previously recorded care conference transcripts that involved physicians and families from 2015 to 2019. We focused on decision-making discussions examining instances of nudging, namely salience, framing, options, default, endowment, commission, omission, recommend, expert opinion, certainty, and social norms. Nudging instances were categorized by decision type, including tracheostomy, goals of care, or procedures. SETTING: Single-center quaternary pediatric facility with general and cardiac ICUs. PATIENTS: None. INTERVENTIONS: None. MEASUREMENTS: We assessed the pattern and frequency of nudges in each transcript. MAIN RESULTS: Sixty-three of the 70 transcripts contained SDM episodes. These episodes represented a total of 11 decision categories based on the subject matter of nudging instances, with 308 decision episodes across all transcripts (median [interquartile range] 5 [4-6] per conference). Tracheostomy was the most frequently discussed decision. A total of 1096 nudging instances were identified across the conferences, with 8 (6-10) nudge types per conference. The most frequent nudging strategy used was gain frame (203/1096 [18.5%]), followed by loss frame (150/1096 [13.7%]). CONCLUSIONS: Nudging is routinely employed by clinicians to guide decision-making, primarily through gain or loss framing. This retrospective analysis aids in understanding nudging in care conferences: it offers insight into potential risks and benefits of these techniques; it highlights ways in which their application has been used by caregivers; and it may be a resource for future trainee curriculum development.