Preclinical studies show that Co-STARs combine the advantages of chimeric antigen and T cell receptors for the treatment of tumors with low antigen densities.

Two types of engineered T cells have been successfully used to treat patients with cancer, one with an antigen recognition domain derived from antibodies [chimeric antigen receptors (CARs)] and the other derived from T cell receptors (TCRs). CARs use high-affinity antigen-binding domains and costimulatory domains to induce T cell activation but can only react against target cells with relatively high amounts of antigen. TCRs have a much lower affinity for their antigens but can react against target cells displaying only a few antigen molecules. Here, we describe a new type of receptor, called a Co-STAR (for costimulatory synthetic TCR and antigen receptor), that combines aspects of both CARs and TCRs. In Co-STARs, the antigen-recognizing components of TCRs are replaced by high-affinity antibody fragments, and costimulation is provided by two modules that drive NF-κB signaling (MyD88 and CD40). Using a TCR-mimic antibody fragment that targets a recurrent p53 neoantigen presented in a common human leukocyte antigen (HLA) allele, we demonstrate that T cells equipped with Co-STARs can kill cancer cells bearing low densities of antigen better than T cells engineered with conventional CARs and patient-derived TCRs in vitro. In mouse models, we show that Co-STARs mediate more robust T cell expansion and more durable tumor regressions than TCRs similarly modified with MyD88 and CD40 costimulation. Our data suggest that Co-STARs may have utility for other peptide-HLA antigens in cancer and other targets where antigen density may limit the efficacy of engineered T cells.

mRNA-encoded Cas13 treatment of Influenza via site-specific degradation of genomic RNA.

The CRISPR-Cas13 system has been proposed as an alternative treatment of viral infections. However, for this approach to be adopted as an antiviral, it must be optimized until levels of efficacy rival or exceed the performance of conventional approaches. To take steps toward this goal, we evaluated the influenza viral RNA degradation patterns resulting from the binding and enzymatic activity of mRNA-encoded LbuCas13a and two crRNAs from a prior study, targeting PB2 genomic and messenger RNA. We found that the genome targeting guide has the potential for significantly higher potency than originally detected, because degradation of the genomic RNA is not uniform across the PB2 segment, but it is augmented in proximity to the Cas13 binding site. The PB2 genome targeting guide exhibited high levels (>1 log) of RNA degradation when delivered 24 hours post-infection in vitro and maintained that level of degradation over time, with increasing multiplicity of infection (MOI), and across modern influenza H1N1 and H3N2 strains. Chemical modifications to guides with potent LbuCas13a function, resulted in nebulizer delivered efficacy (>1-2 log reduction in viral titer) in a hamster model of influenza (Influenza A/H1N1/California/04/09) infection given prophylactically or as a treatment (post-infection). Maximum efficacy was achieved with two doses, when administered both pre- and post-infection. This work provides evidence that mRNA-encoded Cas13a can effectively mitigate Influenza A infections opening the door to the development of a programmable approach to treating multiple respiratory infections.

Harnessing EHR data for health research.

With the increasing availability of rich, longitudinal, real-world clinical data recorded in electronic health records (EHRs) for millions of patients, there is a growing interest in leveraging these records to improve the understanding of human health and disease and translate these insights into clinical applications. However, there is also a need to consider the limitations of these data due to various biases and to understand the impact of missing information. Recognizing and addressing these limitations can inform the design and interpretation of EHR-based informatics studies that avoid confusing or incorrect conclusions, particularly when applied to population or precision medicine. Here we discuss key considerations in the design, implementation and interpretation of EHR-based informatics studies, drawing from examples in the literature across hypothesis generation, hypothesis testing and machine learning applications. We outline the growing opportunities for EHR-based informatics studies, including association studies and predictive modeling, enabled by evolving AI capabilities-while addressing limitations and potential pitfalls to avoid.

Inter- and intraspecific variability of total mercury concentrations in bats of Texas (USA).

Exposure to mercury (Hg) may cause deleterious health effects in wildlife, including bats. Texas produces more Hg pollution than any other state in the United States, yet only one study has examined Hg accumulation in bats. This study measured the concentration of total Hg (THg) in fur (n = 411) collected from ten bat species across 32 sites in eastern and central Texas, USA. Fur THg concentrations were compared among species, and when samples sizes were large enough, between sex and life stage within a species, and the proximity to coal-fired power plants. For all sites combined and species with a sample size ≥ 8, mean THg concentrations (µg/g dry weight) were greatest in tri-colored bats (Perimyotis subflavus; 6.04), followed by evening bats (Nycticeius humeralis; 5.89), cave myotis (Myotis velifer; 2.11), northern yellow bats (Lasiurus intermedius; 1.85), Brazilian free-tailed bats (Tadarida brasiliensis; 1.03), and red bats (Lasiurus borealis/blossevillii; 0.974), and lowest in hoary bats (Lasiurus cinereus; 0.809). Within a species, fur THg concentrations did not significantly vary between sex for the five examined species (red bat, northern yellow bat, cave myotis, evening bat, Brazilian free-tailed bat) and only between life stage in evening bats. Site variations in fur THg concentrations were observed for evening bats, tri-colored bats, and Brazilian free-tailed bats. Evening bats sampled closer to point sources of Hg pollution had greater fur THg concentrations than individuals sampled further away. Sixteen percent of evening bats and 8.7% of tri-colored bats had a fur THg concentration exceeding the 10 µg/g toxicity threshold level, suggesting that THg exposure may pose a risk to the health of bats in Texas, particularly those residing in east Texas and on the upper Gulf coast. The results of this study can be incorporated into future management and recovery plans for bats in Texas.

Flow Cytometry Analysis of Microglial Phenotypes in the Murine Brain During Aging and Disease.

Microglia, the brain's primary resident immune cell, exists in various phenotypic states depending on intrinsic and extrinsic signaling. Distinguishing between these phenotypes can offer valuable biological insights into neurodevelopmental and neurodegenerative processes. Recent advances in single-cell transcriptomic profiling have allowed for increased granularity and better separation of distinct microglial states. While techniques such as immunofluorescence and single-cell RNA sequencing (scRNA-seq) are available to differentiate microglial phenotypes and functions, these methods present notable limitations, including challenging quantification methods, high cost, and advanced analytical techniques. This protocol addresses these limitations by presenting an optimized cell preparation procedure that prevents ex vivo activation and a flow cytometry panel to distinguish four distinct microglial states from murine brain tissue. Following cell preparation, fluorescent antibodies were applied to label 1) homeostatic, 2) disease-associated (DAM), 3) interferon response (IRM), and 4) lipid-droplet accumulating (LDAM) microglia, based on gene markers identified in previous scRNA-Seq studies. Stained cells were analyzed by flow cytometry to assess phenotypic distribution as a function of age and sex. A key advantage of this procedure is its adaptability, allowing the panel provided to be enhanced using additional markers with an appropriate cell analyzer (i.e., Cytek Aurora 5 laser spectral flow cytometer) and interrogating different brain regions or disease models. Additionally, this protocol does not require microglial cell sorting, resulting in a relatively quick and straightforward experiment. Ultimately, this protocol can compare the distribution of microglial phenotypic states between various experimental groups, such as disease state or age, with a lower cost and higher throughput than scRNA-seq. Key features • Analysis of microglial phenotypes from murine brain without the need for cell sorting, imaging, or scRNA-seq. • This protocol can distinguish between homeostatic, disease-associated (DAM), lipid-droplet accumulating (LDAM), and interferon response (IRM) microglia from any murine brain region and/or disease model of interest. • This protocol can be modified to incorporate additional markers of interest or dyes when using a cell analyzer capable of multiple color detections.

CD11c-expressing microglia are transient, driven by interactions with apoptotic cells.

Microglia, the parenchymal macrophage of the central nervous system serve crucial remodeling functions throughout development. Microglia are transcriptionally heterogenous, suggesting that distinct microglial states confer discrete roles. Currently, little is known about how dynamic these states are, the cues that promote them, or how they impact microglial function. In the developing retina, we previously found a significant proportion of microglia express CD11c (Integrin αX, complement receptor 4, Itgax ) which has also been reported in other developmental and disease contexts. Here, we sought to understand the regulation and function of CD11c+ microglia. We found that CD11c+ microglia track with prominent waves of neuronal apoptosis in postnatal retina. Using genetic fate mapping, we provide evidence that microglia transition out of the CD11c state to return to homeostasis. We show that CD11c+ microglia have elevated lysosomal content and contribute to the clearance of apoptotic neurons, and found that acquisition of CD11c expression is, in part, dependent upon the TAM receptor Axl. Using selective ablation, we found CD11c+ microglia are not uniquely critical for phagocytic clearance of apoptotic cells. Together, our data suggest CD11c+ microglia are a transient state induced by developmental apoptosis rather than a specialized subset mediating phagocytic elimination.

Elevated unanticipated acoustic startle reactivity in dyslexia.

People with dyslexia, a neurodevelopmental disorder of reading, are highly attuned to the emotional world. Compared with their typically developing peers, children with dyslexia exhibit greater autonomic nervous system reactivity and facial behaviour to emotion- and empathy-inducing film clips. Affective symptoms, such as anxiety, are also more common in children with dyslexia than in those without. Here, we investigated whether the startle response, an automatic reaction that lies at the interface of emotion and reflex, is elevated in dyslexia. We measured facial behaviour, electrodermal reactivity (a sympathetic nervous system measure) and emotional experience in response to a 100 ms, 105 dB unanticipated acoustic startle task in 30 children with dyslexia and 20 comparison children without dyslexia (aged 7-13) who were matched on age, sex and nonverbal reasoning. Our results indicated that the children with dyslexia had greater total facial behaviour and electrodermal reactivity to the acoustic startle task than the children without dyslexia. Across the sample, greater electrodermal reactivity during the startle predicted greater parent-reported anxiety symptoms. These findings contribute to an emerging picture of heightened emotional reactivity in dyslexia and suggest accentuated sympathetic nervous system reactivity may contribute to the elevated anxiety that is often seen in this population.

Assessment of Erythrocyte Transketolase, Whole Blood Thiamine Diphosphate, and Human Milk Thiamine Concentrations to Identify Infants and Young Children Responding Favorably to Therapeutic Thiamine Administration: Findings from the Lao Thiamine Study, a Prospective Cohort Study.

Background: There is limited information on relationships among biomarkers of thiamine status (whole blood thiamine diphosphate [ThDP], erythrocyte transketolase activity coefficient [ETKac], and human milk thiamine [MTh]) and clinical manifestations of thiamine deficiency. Objectives: This study aimed to explore correlations among these biomarkers and thiamine responsive disorders (TRDs), a diagnosis based on favorable clinical response to thiamine. Methods: Hospitalized infants and young children (aged 21 d to <18 mo) with respiratory, cardiac, and/or neurological symptoms suggestive of thiamine deficiency were treated with parenteral thiamine (100 mg daily) for ≥3 d alongside other treatments and re-examined systematically. Clinical case reports were reviewed by 3 pediatricians, who determined TRD or non-TRD status. Children in a community comparison group were matched by age, sex, and residence. Venous whole blood ThDP and MTh were determined by high-performance liquid chromatography fluorescence detection and ETKac in washed erythrocytes by ultraviolet spectrophotometry. Associations between biomarkers were assessed using Spearman correlations, and biomarker cutoffs predictive of TRD and ETKac >1.25 were explored using area under the receiver operating characteristic curve framework. Results: Thiamine biomarkers were available for 287 hospitalized children and 228 community children (mean age 4.7 mo; 59.4% male). Median (interquartile range [IQR]) ThDP and ETKac were 66.9 nmol/L (IQR: 41.4, 96.9 nmol/L) and 1.25 nmol/L (IQR: 1.11, 1.48 nmol/L), respectively, among hospitalized children, and 64.1 nmol/L (IQR: 50.0, 85.3 nmol/L) and 1.22 nmol/L (IQR: 1.12, 1.37 nmol/L) among 228 community children (P > 0.05 for both). Forty-five percent of breastfeeding mothers of infants <6 mo had MTh <90 µg/L. ThDP and ETKac, but not MTh, were significantly different between 152 children with TRD and 122 without TRD, but overlapping distributions undermined prediction of individual responses to thiamine. Conclusions: Although ETKac, ThDP, and MTh are useful biomarkers of population thiamine status, none of the biomarkers reliably identified individual children with TRD. ThDP is more practical for population assessment because preparing washed erythrocytes is not required.This trial was registered at clinicaltrials.gov as NCT03626337.

Insufficient and biased representation of species geographic responses to climate change.

The geographic redistributions of species due to a rapidly changing climate are poised to perturb ecological communities and significantly impact ecosystems and human livelihoods. Effectively managing these biological impacts requires a thorough understanding of the patterns and processes of species geographic range shifts. While substantial recent redistributions have been identified and recognized to vary by taxon, region, and range geometry, there are large gaps and biases in the available evidence. Here, we use the largest compilation of geographic range change observations to date, comprised of 33,016 potential redistributions across 12,009 species, to formally assess within- and cross-species coverage and biases and to motivate future data collection. We find that species coverage varies strongly by taxon and underrepresents species at high and low latitudes. Within species, assessments of potential redistributions came from parts of their geographic range that were highly uneven and non-representative. For most species and taxa, studies were strongly biased toward the colder parts of species' distributions and thus significantly underrepresented populations that might get pushed beyond their maximum temperature limits. Coverage of potential leading and trailing geographic range edges under a changing climate was similarly uneven. Only 8% of studied species were assessed at both high and low latitude and elevation range edges, with most only covered at one edge. This suggests that substantial within-species biases exacerbate the considerable geographic and taxonomic among-species unevenness in evidence. Our results open the door for a more quantitative accounting for existing knowledge biases in climate change ecology and a more informed management and conservation. Our findings offer guidance for future data collection that better addresses information gaps and provides a more effective foundation for managing the biological impacts of climate change.

O le tagata ma lona aiga, o le tagata ma lona fa'asinomaga (Every person belongs to a family and every family belongs to a person): Development of a parenting framework for adolescent mental wellbeing in American Samoa.

American Samoan adolescents experience a high prevalence of mental health problems, including depression, anxiety, substance use, and suicidal thoughts and behaviors. To complement existing health system efforts, family-based interventions may be a feasible, cost-effective, and relevant opportunity to promote mental health. This community-partnered, qualitative study aimed to: (1) identify potential family-related psychosocial protective factors for adolescent mental health and (2) develop a framework for a parenting program to promote adolescent mental health in American Samoa. Applying the fa'afaletui framework developed for research in Samoan communities, which emphasizes the importance of weaving a range of community member perspectives to reach consensus, semi-structured in-depth interviews with adult key informants (n=28) were conducted between October 2020 and February 2021. Results were validated through five focus groups with Samoan adolescents (n=35) between May and June 2022. Adult participants were sampled for diversity in profession, age, gender, education, and region of residence; adolescent participants were sampled for diversity in gender. Participants were recruited using personal networks and snowball sampling; adolescent participants also responded to Facebook advertising. The semi-structured interviews focused on broad topics including common mental health problems, contributors to mental illness, and potential interventions, among others. Transcripts were coded in duplicate and analyzed using deductive thematic analysis. Themes were collaboratively mapped onto an adapted fonofale model, an existing framework for Pacific Island health research. Six themes described key practices: (1) provide emotional safety and security; (2) provide physical safety and security; (3) encourage sense of self; (4) strengthen intergenerational communication skills; (5) prioritize quality time; and (6) cultivate healthy coping strategies. Participants also expressed the importance of a supportive environment grounded in culture, family and community, and caregiver mental health. These results provide an initial step to identify family-focused factors that promote adolescent mental health in American Samoa and categorize them into a framework to inform intervention development. Drawing on a collaborative and community-partnered process, these findings provide the first evidence-based framework to develop a parenting program to promote adolescent mental wellbeing and resilience in Samoan communities.

Urinary extracellular vesicle-derived miR-126-3p predicts lymph node invasion in patients with high-risk prostate cancer.

To investigate extracellular vesicles (EVs), biomarkers for predicting lymph node invasion (LNI) in patients with high-risk prostate cancer (HRPCa), plasma, and/or urine samples were prospectively collected from 45 patients with prostate cancer (PCa) and five with benign prostatic hyperplasia (BPH). Small RNA sequencing was performed to identify miRNAs in the EVs. All patients with PCa underwent radical prostatectomy and extended pelvic lymph node dissection. Differentially expressed miRNAs were identified in patients with and without pathologically-verified LNI. The candidate miRNAs were validated in low-risk prostate cancer (LRPCa) and BPH. Four miRNA species (e.g., miR-126-3p) and three miRNA species (e.g., miR-27a-3p) were more abundant in urinary and plasma EVs, respectively, of patients with PCa. None of these miRNA species were shared between urinary and plasma EVs. miR-126-3p was significantly more abundant in patients with HR PCa with LNI than in those without (P = 0.018). miR-126-3p was significantly more abundant in the urinary EVs of patients with HRPCa than in those with LRPCa (P = 0.017) and BPH (P = 0.011). In conclusion, urinary EVs-derived miR-126-3p may serve as a good biomarker for predicting LNI in patients with HRPCa.

Puberty classifications in beef heifers are moderately to highly heritable and associated with candidate genes related to cyclicity and timing of puberty.

Introduction: Pubertal attainment is critical to reproductive longevity in heifers. Previously, four heifer pubertal classifications were identified according to attainment of blood plasma progesterone concentrations > 1 ng/ml: 1) Early; 2) Typical; 3) Start-Stop; and 4) Non-Cycling. Early and Typical heifers initiated and maintained cyclicity, Start-Stop started and then stopped cyclicity and Non-Cycling never initiated cyclicity. Start-Stop heifers segregated into Start-Stop-Discontinuous (SSD) or Start-Stop-Start (SSS), with SSD having similar phenotypes to Non-Cycling and SSS to Typical heifers. We hypothesized that these pubertal classifications are heritable, and loci associated with pubertal classifications could be identified by genome wide association studies (GWAS). Methods: Heifers (n = 532; 2017 - 2022) genotyped on the Illumina Bovine SNP50 v2 or GGP Bovine 100K SNP panels were used for variant component estimation and GWAS. Heritability was estimated using a univariate Bayesian animal model. Results: When considering pubertal classifications: Early, Typical, SSS, SSD, and Non-Cycling, pubertal class was moderately heritable (0.38 ± 0.08). However, when heifers who initiated and maintained cyclicity were compared to those that did not cycle (Early+Typical vs. SSD+Non-Cycling) heritability was greater (0.59 ± 0.19). A GWAS did not identify single nucleotide polymorphisms (SNPs) significantly associated with pubertal classifications, indicating puberty is a polygenic trait. A candidate gene approach was used, which fitted SNPs within or nearby a set of 71 candidate genes previously associated with puberty, PCOS, cyclicity, regulation of hormone secretion, signal transduction, and methylation. Eight genes/regions were associated with pubertal classifications, and twenty-two genes/regions were associated with whether puberty was attained during the trial. Additionally, whole genome sequencing (WGS) data on 33 heifers were aligned to the reference genome (ARS-UCD1.2) to identify variants in FSHR, a gene critical to pubertal attainment. Fisher's exact test determined if FSHR SNPs segregated by pubertal classification. Two FSHR SNPs that were not on the bovine SNP panel were selected for additional genotyping and analysis, and one was associated with pubertal classifications and whether they cycled during the trial. Discussion: In summary, these pubertal classifications are moderately to highly heritable and polygenic. Consequently, genomic tools to inform selection/management of replacement heifers would be useful if informed by SNPs associated with cyclicity and early pubertal attainment.

Cannibalism and competition can increase parasite abundance for parasites with complex life history strategies.

Ecological interactions among hosts are critical to consider when predicting disease dynamics. Most theory predicts that intraguild predation (IGP) and cannibalism negatively impact parasite populations, but this is based primarily on assumptions of simple or single-host life cycles. Here we investigate the effects of cannibalism in a size-structured host population on two digenean trematodes that have complex, multihost life cycles. A high incidence of cannibalism among paratenic hosts produced higher parasite infection loads and abundance, whereas cannibalism among obligate hosts reduced parasite abundances. We attributed this difference to trophic transmission aggregating parasites in larger, potentially fitter hosts and also to transmission among paratenic hosts via cannibalism. Moreover, we found evidence of indirect competitive interactions between parasites that can also increase infections at small scales. Our results show there are multiple mechanisms through which high cannibalism environments can benefit parasites that use paratenic hosts and trophic transfer to complete their life cycles.

A series of pyrimidine-based antifungals with anti-mold activity disrupt ER function in Aspergillus fumigatus.

Fungal infections are a major contributor to morbidity and mortality among immunocompromised populations. Moreover, fungal disease caused by molds are difficult to treat and are associated with particularly high mortality. To address the need for new mold-active antifungal drugs, we performed a high-throughput screen with Aspergillus fumigatus, the most common pathogenic mold. We identified a novel, pyrimidine-based chemical scaffold with broad-spectrum antifungal activity including activity against several difficult-to-treat molds. A chemical genetics screen of Saccharomyces cerevisiae suggested that this compound may target the endoplasmic reticulum (ER) and perturb ER function and/or homeostasis. Consistent with this model, this compound induces the unfolded protein response and inhibits secretion of A. fumigatus collagenases. Initial cytotoxicity and pharmacokinetic studies show favorable features including limited mammalian cell toxicity and bioavailability in vivo. Together, these data support the further medicinal chemistry and pre-clinical development of this pyrimidine scaffold toward more effective treatments for life-threatening invasive mold infections.IMPORTANCEInvasive fungal diseases are life-threatening infections caused by fungi in immunocompromised individuals. Currently, there are only three major classes of antifungal drugs available to treat fungal infections; however, these options are becoming even more limited with the global emergence of antifungal drug resistance. To address the need for new antifungal therapies, we performed a screen of chemical compounds and identified a novel molecule with antifungal activity. Initial characterization of this compound shows drug-like features and broad-spectrum activity against medically important fungi. Together, our results support the continued development of this compound as a potential future therapy for these devastating fungal infections.

Fe/Thiol Cooperative Hydrogen Atom Transfer Olefin Hydrogenation: Mechanistic Insights That Inform Enantioselective Catalysis.

Asymmetric hydrogenation of activated olefins using transition metal catalysis is a powerful tool for the synthesis of complex molecules, but traditional metal catalysts have difficulty with enantioselective reduction of electron-neutral, electron-rich, and minimally functionalized olefins. Hydrogenation based on radical, metal-catalyzed hydrogen atom transfer (mHAT) mechanisms offers an outstanding opportunity to overcome these difficulties, enabling the mild reduction of these challenging olefins with selectivity that is complementary to traditional hydrogenations with H2. Further, mHAT presents an opportunity for asymmetric induction through cooperative hydrogen atom transfer (cHAT) using chiral thiols. Here, we report insights from a mechanistic study of an iron-catalyzed achiral cHAT reaction and leverage these insights to deliver stereocontrol from chiral thiols. Kinetic analysis and variation of silane structure point to the transfer of hydride from silane to iron as the likely rate-limiting step. The data indicate that the selectivity-determining step is quenching of the alkyl radical by thiol, which becomes a more potent H atom donor when coordinated to iron(II). The resulting iron(III)-thiolate complex is in equilibrium with other iron species, including FeII(acac)2, which is shown to be the predominant off-cycle species. The enantiodetermining nature of the thiol trapping step enables enantioselective net hydrogenation of olefins through cHAT using a commercially available glucose-derived thiol catalyst with up to 80:20 enantiomeric ratio. To the best of our knowledge, this is the first demonstration of asymmetric hydrogenation via iron-catalyzed mHAT. These findings advance our understanding of cooperative radical catalysis and act as a proof of principle for the development of enantioselective iron-catalyzed mHAT reactions.

Utility of ADC Values for Differentiating Uterine Sarcomas From Leiomyomas: Systematic Review and Meta-Analysis.

Background: Uterine sarcomas are rare; however, they display imaging features that overlap those of leiomyomas. The potential for undetected uterine sarcomas is clinically relevant because minimally invasive treatment of leiomyomas may lead to cancer dissemination. ADC values have shown potential for differentiating benign and malignant uterine masses. Objective: The purpose of this study was to perform a systematic review of the diagnostic performance of ADC values in differentiating uterine sarcomas from leiomyomas. Evidence acquisition: We searched three electronic databases (MEDLINE, EMBASE, and Cochrane databases) for studies distinguishing uterine sarcomas from leiomyomas using MRI, including ADC, with pathologic tissue confirmation or imaging follow-up as the reference standard. Data extraction and QUADAS-2 quality assessment were performed. Sensitivity and specificity were pooled using hierarchic models, including bivariate and hierarchic summary ROC models. Metaregression was used to assess the impact of various factors on heterogeneity. Evidence synthesis: Twenty-one studies met study inclusion criteria. Pooled sensitivity and specificity were 89% (95% CI, 82-94%) and 86% (95% CI, 78-92%), respectively. Area under the summary ROC curve was 94% (95% CI, 92-96%). Context of ADC interpretation (i.e., standalone vs part of multiparametric MRI [mpMRI]) was the only factor found to account significantly for heterogeneity (p = .01). Higher specificity (95% [95% CI, 92-99%] vs 82% [95% CI, 75-89%]) and similar sensitivity (94% [95% CI, 89-99%] vs 88% [95% CI, 82-93%]) were observed when ADC was evaluated among mpMRI features as compared with standalone ADC assessment. ADC cutoff values ranged (0.87-1.29 × 10-3 mm2/s) but were not associated with statistically different performance (p = .37). Pooled mean ADC values in sarcomas and leiomyomas were 0.904 × 10-3 mm2/s and 1.287 × 10-3 mm2/s, respectively. Conclusion: As part of mpMRI evaluation of uterine masses, mass ADC value less than 0.904 × 10-3 mm2/s may be a useful test-positive threshold for uterine sarcoma, consistent with a prior expert consensus statement. Institutional protocols may influence locally selected ADC values. Clinical Impact: Using ADC as part of mpMRI assessment improves detection of uterine sarcoma, which could influence candidate selection for minimally invasive treatments.

Sarbecovirus disease susceptibility is conserved across viral and host models.

Coronaviruses have caused three severe epidemics since the start of the 21st century: SARS, MERS and COVID-19. The severity of the ongoing COVID-19 pandemic and increasing likelihood of future coronavirus outbreaks motivates greater understanding of factors leading to severe coronavirus disease. We screened ten strains from the Collaborative Cross mouse genetic reference panel and identified strains CC006/TauUnc (CC006) and CC044/Unc (CC044) as coronavirus-susceptible and resistant, respectively, as indicated by variable weight loss and lung congestion scores four days post-infection. We generated a genetic mapping population of 755 CC006xCC044 F2 mice and exposed the mice to one of three genetically distinct mouse-adapted coronaviruses: clade 1a SARS-CoV MA15 (n=391), clade 1b SARS-CoV-2 MA10 (n=274), and clade 2 HKU3-CoV MA (n=90). Quantitative trait loci (QTL) mapping in SARS-CoV MA15- and SARS-CoV-2 MA10-infected F2 mice identified genetic loci associated with disease severity. Specifically, we identified seven loci associated with variation in outcome following infection with either virus, including one, HrS43, that is present in both groups. Three of these QTL, including HrS43, were also associated with HKU3-CoV MA outcome. HrS43 overlaps with a QTL previously reported by our lab that is associated with SARS-CoV MA15 outcome in CC011xCC074 F2 mice and is also syntenic with a human chromosomal region associated with severe COVID-19 outcomes in humans GWAS. The results reported here provide: (a) additional support for the involvement of this locus in SARS-CoV MA15 infection, (b) the first conclusive evidence that this locus is associated with susceptibility across the Sarbecovirus subgenus, and (c) demonstration of the relevance of mouse models in the study of coronavirus disease susceptibility in humans.

Sexual Victimization, Emotion Dysregulation, and Sexual Consent Feelings and Communication During a Recent Sexual Encounter.

Sexual consent has been a major focus of campus campaigns to reduce sexual violence (SV). However, these campaigns often educate students about consent with little attention to the complex ways consent can be experienced, expressed, and interpreted by others. Further, little research has focused on the consent feelings and communication cues of students who have a history of SV, nor have studies examined how the ability to attend to and regulate emotions relates to internal feelings or external communication of consent. This secondary analysis examined SV histories, emotion dysregulation, and internal and external consent cues in a sample of 610 college students (72% women) who completed an online self-report survey. Findings revealed that students with SV histories (n = 257) reported greater emotion dysregulation, lower internal consent, and greater use of passive external consent cues compared to students without SV histories; greater emotion dysregulation was associated with lower internal consent. In a path model, SV history was indirectly related to use of direct nonverbal and passive consent cues through greater emotion dysregulation and lower internal consent. Contrary to expectations, higher internal consent was associated with greater use of passive external consent cues. Consent programming could be augmented to encourage attention to and regulation of emotions in sexual situations to improve communication and sexual well-being.

Biological variation in cervical spinal cord MRI morphometry in healthy individuals and people with multiple sclerosis.

BACKGROUND AND PURPOSE: Conclusions from prior literature regarding the impact of sex, age, and height on spinal cord (SC) MRI morphometrics are conflicting, while the effect of body weight on SC morphometrics has been found to be nonsignificant. The purpose of this case-control study is to assess the associations between cervical SC MRI morphometric parameters and age, sex, height, and weight to establish their potential role as confounding variables in a clinical study of people with multiple sclerosis (MS) compared to a cohort of healthy volunteers. METHODS: Sixty-nine healthy volunteers and 31 people with MS underwent cervical SC MRI at 3 Tesla field strength. Images were centered at the C3/C4 intervertebral disc and processed using Spinal Cord Toolbox v.4.0.2. Mixed-effects linear regression models were used to evaluate the effects of biological variables and disease status on morphometric parameters. RESULTS: Sex, age, and height had significant effects on cord and gray matter (GM) cross-sectional area (CSA) as well as the GM:cord CSA ratio. There were no significant effects of body weight on morphometric parameters. The effect of MS disease duration on cord CSA in the C4 level was significant when controlling for all other variables. CONCLUSIONS: Studies of disease-related changes in SC morphometry should control for sex, age, and height to account for physiological variation.