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* Context.--Rapid advancements in the understanding and manipulation of tumor-immune interactions have led to the approval of immune therapies for patients with non-small cell lung cancer. Certain immune checkpoint inhibitor therapies require the use of companion diagnostics, but methodologic variability has led to uncertainty around test selection and implementation in practice. Objective.--To develop evidence-based guideline recommendations for the testing of immunotherapy/immunomodulatory biomarkers, including programmed death ligand-1 (PD-L1) and tumor mutation burden (TMB), in patients with lung cancer. Design.--The College of American Pathologists convened a panel of experts in non-small cell lung cancer and biomarker testing to develop evidence-based recommendations in accordance with the standards for trustworthy clinical practice guidelines established by the National Academy of Medicine. A systematic literature review was conducted to address 8 key questions. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, recommendations were created from the available evidence, certainty of that evidence, and key judgments as defined in the GRADE Evidence to Decision framework. Results.--Six recommendation statements were developed. Conclusions.--This guideline summarizes the current understanding and hurdles associated with the use of PD-L1 expression and TMB testing for immune checkpoint inhibitor therapy selection in patients with advanced non-small cell lung cancer and presents evidence-based recommendations for PD-L1 and tMb testing in the clinical setting. doi: 10.5858/arpa.2023-0536-CP), The advent of immune modulatory therapy has led to a radical shift in the treatment paradigm for patients with a wide range of cancers. The clinical impact of these therapies, [...]

* Context.--In 2018 the College of American Pathologists Diagnostic Immunology and Flow Cytometry Committee designed and implemented a new plasma cell neoplasia flow cytometry proficiency testing program--PCNEO--to allow clinical flow cytometry laboratories to monitor and assess their performance compared with a peer group. Objective.--To report the results from the first 4 years of the PCNEO program. Design.--Program participants were sent 2 sets of challenges per year, each including 1 wet challenge and 2 dry challenges, with associated clinical and laboratory findings. The wet challenges were composed of myeloma cell line specimens (with or without dilution in preserved whole blood) for flow cytometric analysis. The dry (paper) challenges were composed of clinical case summaries and images of flow cytometric test results from various flow cytometry laboratories of committee members. Results.--A total of 116 to 145 laboratories from 17 countries enrolled in the proficiency testing program. For the wet challenges, almost all participants (97%-100%; cumulative, 98.2%) correctly identified the presence of neoplastic plasma cell populations based on flow cytometric analysis of undiluted myeloma cell lines. Slightly fewer participants (89.0%-97.4%; cumulative, 95.2%) correctly identified the presence of neoplastic plasma cell populations based on flow cytometric analysis of diluted myeloma cell lines (10% or 50% dilutions into peripheral blood) intended to better represent a typical clinical sample. There was generally agreement among 80% or more of participants for positive or negative staining for CD38, CD138, CD19, CD20, and surface and cytoplasmic k and X light chains. Similarly, 84% to 100% of participants were able to correctly identify the presence of neoplastic plasma cell populations in paper challenges, including the presence of small, neoplastic plasma cell populations (0.01%-5.0% clonal plasma cells) and the presence of nonneoplastic plasma cell populations (correctly identified by 91 %-96% of participants). Conclusions.--Participant performance in the new proficiency testing program was excellent overall, with the vast majority of participants able to perform flow cytometric analysis and identify neoplastic plasma cell populations and to identify small plasma cell clones or expanded populations of reactive plasma cells in dry challenge flow cytometry results. This program will allow laboratories to verify the accuracy of their testing program and test interpretations for the assessment of patients suspected of having a plasma cell neoplasm. (Arch Pathol Lab Med. 2024;148:699-704; doi: 10.5858/arpa. 2023-0035-CP), The Diagnostic Immunology and Flow Cytometry Committee (DIFCC) acts as an expert scientific and educational resource for the College of American Pathologists in diagnostic immunology and flow cytometry clinical testing. [...]

Madagascar reports more human plague (causative agent: Yersinia pestis) cases annually than any other country (1), often several hundred each season (typically September-March) (2). Y. pestis persists in multiple rural [...]

* Context.--Pediatric soft tissue tumors are one of the areas of pediatric pathology that frequently generate consult requests. Evolving classification systems, ancillary testing methods, new treatment options, research enrollment opportunities, and tissue archival processes create additional complexity in handling these unique specimens. Pathologists are at the heart of this critical decision-making, balancing responsibilities to consider expediency, accessibility, and cost-effectiveness of ancillary testing during pathologic examination and reporting. Objective.--To provide a practical approach to handling pediatric soft tissue tumor specimens, including volume considerations, immunohistochemical staining panel recommendations, genetic and molecular testing approaches, and other processes that impact the quality and efficiency of tumor tissue triage. Data Sources.--The World Health Organization Classification of Soft Tissue and Bone Tumors, 5th edition, other recent literature investigating tissue handling, and the collective clinical experience of the group are used in this manuscript. Conclusions.--Pediatric soft tissue tumors can be difficult to diagnose, and evaluation can be improved by adopting a thoughtful, algorithmic approach to maximize available tissue and minimize time to diagnosis. doi: 10.5858/arpa.2022-0364-RA, Pediatric soft tissue tumors comprise a broad spectrum of lesions, including malformative, benign, intermediate, and malignant entities. Although the vast majority are benign, locally aggressive and malignant tumors require careful [...]

Original citation: J Clin Invest. 2024; 134(10):e173278. https://doi.org/10.1172/JCI173278. Citation for this corrigendum: J Clin Invest. 2024;134(16):e185290. https://doi.org/10.1172/JCI185290 During the preparation of this manuscript, Daniel Duprez's information was inadvertently omitted from [...]

Context.--Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) assay reagents are available both with and without supplementation with pyridoxal-5'-phosphate (P5P; the active form of vitamin b6), a catalytic cofactor required for their enzymatic reactions. Nonsupplemented assays may miss ALT or AST elevations in patients with vitamin B6 deficiency. Objective.--To assess awareness and adoption of ALT and AST reagents that are supplemented with P5P. Design.--A 4-question survey about ALT and AST reagent supplementation with P5P was included in the College of American Pathologists General Chemistry and Therapeutic Drugs (C program) proficiency testing 2023 B mailing. Results.--Overall, 38% (1651 of 4304) of responding laboratories reported using ALT and/or AST reagent supplemented with P5P. P5P supplementation was more common for nonacademic hospital/medical center laboratories (44%; 713 of 1629) relative to other settings. Of the laboratories that reported not using P5P-supplemented reagents, few (5%; 141 of 2611) cited plans to convert in the future. Despite the availability of P5P-supplemented reagents from several major assay manufacturers, the most common stated barrier for adoption was that the laboratory's reagent manufacturer does not provide P5P-supplemented reagents. Conclusions.--There is a lack of awareness of the existence and benefits of P5P-supplemented ALT and AST reagents. There is a need for ALT and AST assay manufacturers to clarify and standardize the P5P status of ALT and AST reagents. doi: 10.5858/arpa.2024-0097-CP, Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are liver-associated enzymes commonly used as biomarkers of hepatic injury or disease. Serum or plasma ALT and AST concentrations are typically measured on [...]

STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and the Ivy Glioblastoma Atlas, STING expression was found in myeloid populations and in the perivascular space. The STING agonist 8803 increased median survival in multiple preclinical models of glioblastoma, including QPP8, an immune checkpoint blockade-resistant model, where 100% of mice were cured. Ex vivo flow cytometry profiling during the therapeutic window demonstrated increases in myeloid tumor trafficking and activation, alongside enhancement of [CD8.sup.+] T cell and NK effector responses. Treatment with 8803 reprogrammed microglia to express costimulatory CD80/CD86 and iNOS, while decreasing immunosuppressive CD206 and arginase. In humanized mice, where tumor cell STING is epigenetically silenced, 8803 therapeutic activity was maintained, further attesting to myeloid dependency and reprogramming. Although the combination with a STAT3 inhibitor did not further enhance STING agonist activity, the addition of anti-PD-1 antibodies to 8803 treatment enhanced survival in an immune checkpoint blockade-responsive glioma model. In summary, 8803 as a monotherapy demonstrates marked in vivo therapeutic activity, meriting consideration for clinical translation., Introduction The prognosis of glioblastoma patients is poor, with an approximate median overall survival of 21 months (1). Whereas radiation and chemotherapy are standard treatments at the time of diagnosis, [...]

Trisomy 21 (T21), a recurrent aneuploidy occurring in 1:800 births, predisposes to congenital heart disease (CHD) and multiple extracardiac phenotypes. Despite a definitive genetic etiology, the mechanisms by which T21 perturbs development and homeostasis remain poorly understood. We compared the transcriptome of CHD tissues from 49 patients with T21 and 226 with euploid CHD (eCHD). We resolved cell lineages that misexpressed T21 transcripts by cardiac single-nucleus RNA sequencing and RNA in situ hybridization. Compared with eCHD samples, T21 samples had increased chr21 gene expression; 11-fold-greater levels (P = 1.2 x [10.sup.8]) of SOST (chr17), encoding the Wnt inhibitor sclerostin; and 1.4-fold-higher levels (P = 8.7 x [10.sup.-8]) of the SOST transcriptional activator ZNF467 (chr7). Euploid and T21 cardiac endothelial cells coexpressed SOST and ZNF467; however, T21 endothelial cells expressed 6.9-fold more SOST than euploid endothelial cells (P = 2.7 x [10.sup.-27]). Wnt pathway genes were downregulated in T21 endothelial cells. Expression of DSCAM, residing within the chr21 CHD critical region, correlated with SOST(P = 1.9 x [10.sup.-5]) and ZNF467 (P = 2.9 x [10.sup.-4]). Deletion of DSCAM from T21 endothelial cells derived from human induced pluripotent stem cells diminished sclerostin secretion. As Wnt signaling is critical for atrioventricular canal formation, bone health, and pulmonary vascular homeostasis, we concluded that T21-mediated increased sclerostin levels would inappropriately inhibit Wnt activities and promote Down syndrome phenotypes. These findings imply therapeutic potential for anti-sclerostin antibodies in T21., Introduction Trisomy 21 (T21), the most common genetic cause of syndromic congenital heart disease (CHD), is diagnosed in approximately 5,000 newborns in the US annually. Almost half of affected infants [...]

BACKGROUND. Preclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN)--suggestive of cellular cholesterol accumulation--were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation. METHODS. Monocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples. RESULTS. During a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes--ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression)--and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D. CONCLUSION. These data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis. FUNDING. The MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962., Introduction While hypercholesterolemia is a common feature of patients with type 2 diabetes (T2D), its role in the pathogenesis of this disease is not well established. The negative impact of [...]

Proline substitutions within the coiled-coil rod region of the [beta]-myosin gene (MYH7) are the predominant mutations causing Laing distal myopathy (MPD1), an autosomal dominant disorder characterized by progressive weakness of distal/proximal muscles. We report that the MDP1 mutation R1500P, studied in what we believe to be the first mouse model for the disease, adversely affected myosin motor activity despite being in the structural rod domain that directs thick filament assembly. Contractility experiments carried out on isolated mutant muscles, myofibrils, and myofibers identified muscle fatigue and weakness phenotypes, an increased rate of actin- myosin detachment, and a conformational shift of the myosin heads toward the more reactive disordered relaxed (DRX) state, causing hypercontractility and greater ATP consumption. Similarly, molecular analysis of muscle biopsies from patients with MPD1 revealed a significant increase in sarcomeric DRX content, as observed in a subset of myosin motor domain mutations causing hypertrophic cardiomyopathy. Finally, oral administration of MYK-581, a small molecule that decreases the population of heads in the DRX configuration, significantly improved the limited running capacity of the R1500P-transgenic mice and corrected the increased DRX state of the myofibrils from patients. These studies provide evidence of the molecular pathogenesis of proline rod mutations and lay the groundwork for the therapeutic advancement of myosin modulators., Introduction Laing distal myopathy, also called myopathy distal type 1 (MPD1), is an autosomal dominant disease with variable onset and phenotypic severity. Typically, MPD1 begins with weakness of the anterior [...]

Martineau's Reputation in Her Own Day Although Harriet Martineau is underappreciated today, her writings were widely read during her lifetime, and she was extremely influential in her own time. She [...]

Two separate bodies of literature point to the link between family bereavement and cardiovascular health and between sleep quality and cardiovascular outcomes. However, less is known about the joint influence of family bereavement and sleep quality on cardiovascular functioning. The aims of this study were to examine the relationships between experiencing the death of a family member and heart rate variability (HRV) and to further explore whether these associations differ by sleep quality. Using data from the Midlife in the United States (MIDUS) Biomarker Project, the sample for this study included respondents who experienced the death of an immediate family member - father, mother, spouse, sibling, or child - within a year before the Biomarker project and those who did not experience any deaths (N = 962). We used two measures of HRV and sleep quality was measured using the Pittsburgh Sleep Quality Index. Results showed that experiencing the death of a family member was associated with worse HRV only among those with poor sleep quality and not for those with good sleep quality. These results suggest that poor sleep quality may indicate psychophysiological vulnerability for those who experienced the death of a family member. Interventions to improve sleep quality could be effective in enhancing cardiovascular health of bereaved individuals., Author(s): Hye Won Chai [sup.1] , Dylan J. Jester [sup.2] [sup.3] , Soomi Lee [sup.4] , Susanna Joo [sup.5] , Debra J. Umberson [sup.1] [sup.6] , David M. Almeida [sup.7] [...]

The suggested overlap between autism spectrum disorder (ASD) and gender dysphoria/incongruence (GD/GI) has been much disputed. This review showed a relationship between ASD traits and GD feelings in the general population and a high prevalence of GD/GI in ASD. Our meta-analyses revealed that the pooled estimate of the prevalence of ASD diagnoses in GD/GI people was 11% (p < .001) and the overall effect size of the difference in ASD traits between GD/GI and control people was significant (g = 0.67, p < .001). Heterogeneity was high in both meta-analyses. We demonstrated that the chances that there is not a link between ASD and GD/GI are negligible, yet the size of it needs further investigation., Author(s): Aimilia Kallitsounaki [sup.1] , David M. Williams [sup.1] Author Affiliations: (1) grid.9759.2, 0000 0001 2232 2818, School of Psychology, University of Kent, Keynes College, , CT2 7NP, Canterbury, Kent, [...]

This study examines the functional histology of the thin-spined porcupine's (Chaetomys subspinosus (Olfers, 1818)) quills and integument, and compares them with the North American porcupine (Erethizon dorsatum (Linnaeus, 1758)) equivalents. Erethizon quills disseminate warnings to potential predators. An olfactory warning is generated by sebaceous glands of the lower back, disseminated by osmetrichial specializations of lower-back quills. Chaetomys skin lacks functional sebaceous glands, and generates no warning odor. Erethizon quills also carry a visual warning, effective even in dim light. Chaetomys quills carry no warning color. The straight, stiff quills of Erethizon are tipped with one-way barbs and can be elevated to 90[degrees]. A protective collagenous spool at the base of the quill prevents back-stabbing on impact. Chaetomys quills lack barbs and the basal collagenous spool is poorly developed. The quill shafts are wavy and angled at the base, allowing them to act as shock absorbers during a fall from a tree. Nevertheless, Chaetomys quills of the head and shoulders can be elevated to 90[degrees] to function as stabbing devices. Major defensive quills of Erethizon protect the back; in Chaetomys, the front. Though both species have 1-3 arrector muscles, they differ in the details of quill stabilization. The Chaetomys quill surface has regional cuticular patterns, of which the distal, longest region is highly pitted. The function of the pitted region remains a mystery. Key words: Chaetomys subspinosus, thin-spined porcupine, Erethizon dorsatum, North American porcupine, functional histology of quills, hair, skin, aposematic signaling, Introduction The functional histology of the skin of the thin-spined porcupine, Chaetomys subspinosus, from Brazil is here described and compared with the skin of Erethizon dorsatum, the North American porcupine. [...]

Predation by crustaceans and echinoderms is a significant driver of mortality for sessile invertebrates in near-shore marine ecosystems. As a response, shellfish growers use predator exclusion cages to grow their product. Oysters grown in these cages and clams in and under nets have been observed to exhibit thinner, brittle shells, which is not optimal for market, nor for those being grown for restoration purposes. Here, the nonconsumptive predator effects of several native and nonnative predators on shell morphology of Crassostrea virginica oyster spat. Juvenile (1-3 mm) seed oysters were exposed separately to chemical cues of five different predators and one nonpredator crab were investigated and compared with control (no exposure) spat. Significant effects of predator presence on the total wet weight (g) of the spat was demonstrated, with the highest increase for spat exposed to black-fingered mud crabs (Panopeus, 1.70 mg [d.sup.-1]) and the biggest decreases for spat exposed to the European green crabs (Carcinus mamas--1.34 mg [d.sup.-1]) and the sea stars (Asterias rubens--1.47 mg [d.sup.-1]). Changes to oyster length (mm) and shell density (crushing resistance) were not significant. Implications for aquaculturists and wild bivalve populations are that growth could be negatively affected by the lack of predators on these important organisms. KEY WORDS: Crassostreci virginica, oysters, spat, crabs, shell growth, shell strength, Asterias rubens, INTRODUCTION As global demand for seafood increases, commercial aquaculture has emerged as one solution to meet this demand. Today, aquaculture has reached parity as a main method of production of [...]

Background: Virtual patient simulations are interactive, computer-based cases. We designed scenarios based on the McGill Simulation Complexity Score (MSCS), a previously described objective complexity score. We aimed to establish validity of the MSCS and introduce a novel learning tool in trauma education at our institution. Methods: After design of an easy and difficult patient scenario, we randomized medical students and residents to each perform 1 of the 2 scenarios. We conducted a 2-way analysis of variance of training level (medical student, resident) and scenario complexity (easy, difficult) to assess their effects on virtual time, the number of steps taken in the scenario, beneficial and harmful actions, and the ratio of beneficial over harmful actions. Results: Virtual patient scenarios were successfully designed using the MSCS. Twenty-four medical students and 12 residents participated in the easy scenario (MSCS = 3), and 27 medical students and 12 residents did the difficult scenario (MSCS = 18). Though beneficial actions were similar between students and residents, sudents performed more harmful actions, particularly when the scenario was difficult. One virtual patient died in the easy scenario and 3 died in the diffcult one (all medical students). Performance varied with level of complexity and there was significant interaction between level of training and number of steps, as well as with number of harmful actions. Decreasing performance with increasing level of complexity, as defined by the MSCS, suggests this score can accurately quantify difficulty. Conclusion: We established validity of the MSCS and showed its successful application on virtual patient scenario design. Contexte : Les simulations medicales virtuelles sont des cas interactifs informatises. Nous avons concu des scenarios en utilisant le score de complexite des simulations McGill (SCSM), un score de complexite objectif decrit precedemment. Nous avons voulu confirmer la validite du SCSM et presenter un nouvel outil d'apprentissage en traumatologie pour notre etablissement. Methodes : Apres avoir concu le scenario d'un cas facile et d'un cas difficile, nous avons assigne aleatoirement des etudiants en medecine et des residents a 1 des 2 scenarios pour qu'ils y travaillent. Nous avons procede a une analyse de la variance a 2 facteurs, formation (etudiant en medecine, resident) et complexite des cas (facile, difficile,) pour mesurer leurs effets sur le temps virtuel, le nombre d'etapes franchies dans le scenario, les interventions benefques et nuisibles et le rapport entre les deux. Resultats : Les scenarios de cas virtuels ont ete concus avec succes a l'aide du SCSM. Vingt-quatre etudiants en medecine et 12 residents ont travaille au scenario facile (SCSM = 3), et 27 etudiants en medecine et 12 residents ont travaille au scenario difficile (SCSM = 18). Meme si les interventions benefques etaient similaires entre les etudiants et les residents, les etudiants ont applique plus d'interventions nuisibles que les residents, particulierement lorsque le scenario etait difficile. Un patient virtuel du scenario facile et 3 du scenario difficile sont decedes (etudiants dans tous les cas). Le rendement a varie selon le degre de complexite et on a note un lien significatif entre le niveau de formation et le nombre d'etapes et de mesures nuisibles. Le fait que le rendement ait ete inversement proportionnel a la complexite definie par le SCSM, suggere que ce dernier mesure avec exactitude le degre de complexite. Conclusion : Nous avons confirme la validite du score SCSM et montre son utilite dans la conception de scenarios de cas virtuels., Virtual patient simulations are interactive, computer -based cases through which trainees can navigate by selecting various management options offered to them. As Cook and colleagues illustrated, (1) in a world [...]

Wnts, cholesterol, and MAPK signaling are essential for development and adult homeostasis. Here, we report that fatty acid hydroxylase domain containing 2 (FAXDC2), a previously uncharacterized enzyme, functions as a methyl sterol oxidase catalyzing C4 demethylation in the Kandutsch-Russell branch of the cholesterol biosynthesis pathway. FAXDC2, a paralog of MSMO1, regulated the abundance of the specific C4-methyl sterols lophenol and dihydro-T-MAS. Highlighting its clinical relevance, FAXDC2 was repressed in Wnt/[beta]-catenin-high cancer xenografts, in a mouse genetic model of Wnt activation, and in human colorectal cancers. Moreover, in primary human colorectal cancers, the sterol lophenol, regulated by FAXDC2, accumulated in the cancerous tissues and not in adjacent normal tissues. FAXDC2 linked Wnts to RTK/MAPK signaling. Wnt inhibition drove increased recycling of RTKs and activation of the MAPK pathway, and this required FAXDC2. Blocking Wnt signaling in Wnt-high cancers caused both differentiation and senescence; and this was prevented by knockout of FAXDC2. Our data show the integration of 3 ancient pathways, Wnts, cholesterol synthesis, and RTK/MAPK signaling, in cellular proliferation and differentiation., Introduction During animal development and in adult stem cell niches, the balance between stemness, proliferation, and differentiation is regulated by Wnt/[beta]-catenin signaling (1, 2). Wnts are secreted palmitoleated glycoproteins that [...]

Pulmonary arterial hypertension (PAH) is a devastating and progressive disease with limited treatment options. Endothelial dysfunction plays a central role in the development and progression of PAH, yet the underlying mechanisms are incompletely understood. The endosome-lysosome system is important to maintain cellular health, and the small GTPase RAB7 regulates many functions of this system. Here, we explored the role of RAB7 in endothelial cell (EC) function and lung vascular homeostasis. We found reduced expression of RAB7 in ECs from patients with PAH. Endothelial haploinsufficiency of RAB7 caused spontaneous pulmonary hypertension (PH) in mice. Silencing of RAB7 in ECs induced broad changes in gene expression revealed via RNA-Seq, and RAB7-silenced ECs showed impaired angiogenesis and expansion of a senescent cell fraction, combined with impaired endolysosomal trafficking and degradation, suggesting inhibition of autophagy at the predegradation level. Furthermore, mitochondrial membrane potential and oxidative phosphorylation were decreased, and glycolysis was enhanced. Treatment with the RAB7 activator ML-098 reduced established PH in rats with chronic hypoxia/ SU5416. In conclusion, we demonstrate for the first time to our knowledge the fundamental impairment of EC function by loss of RAB7, causing PH, and show RAB7 activation to be a potential therapeutic strategy in a preclinical model of PH., Introduction Pulmonary arterial hypertension (PAH) is a severe and fatal condition characterized by increased pulmonary artery (PA) pressure and extensive remodeling of all layers of the PA wall (1, 2). [...]

Since the discovery that cGAS/STING recognizes endogenous DNA released from dying cancer cells and induces type I interferon and antitumor T cell responses, efforts to understand and therapeutically target the STING pathway in cancer have ensued. Relative to other cancer types, the glioma immune microenvironment harbors few infiltrating T cells, but abundant tumor-associated myeloid cells, possibly explaining disappointing responses to immune checkpoint blockade therapies in cohorts of patients with glioblastoma. Notably, unlike most extracranial tumors, STING expression is absent in the malignant compartment of gliomas, likely due to methylation of the STING promoter. Nonetheless, several preclinical studies suggest that inducing cGAS/STING signaling in the glioma immune microenvironment could be therapeutically beneficial, and cGAS/STING signaling has been shown to mediate inflammatory and antitumor effects of other modalities either in use or being developed for glioblastoma therapy, including radiation, tumor-treating fields, and oncolytic virotherapy. In this Review, we discuss cGAS/STING signaling in gliomas, its implications for glioma immunobiology, compartment-specific roles for STING signaling in influencing immune surveillance, and efforts to target STING signaling--either directly or indirectly--for antiglioma therapy., Introduction Cues from the innate immune system determine the priming, recruitment, and functionality of adaptive immunity. This crosstalk is generally mediated through antigen-independent pattern recognition receptor (PRR) signaling and results [...]

At the turn of the 20th century, the newly discovered uses for x-ray technology in medicine and the emerging field of neurosurgery helped lead to the rise of a pivotal [...]

Burkholderia thailandensis, a gram-negative bacterium found in the environment, poses a public health threat both because of its ability to cause infections as an opportunistic pathogen and potential misidentification as [...]

There is substantial comorbidity between autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD), and there are well-documented executive functioning (EF) deficits in both populations. An important question concerns whether EF deficits in children with ASD are related to severity of ASD, ADHD, or both. We examined ADHD and ASD symptoms in relation to ratings of EF in the home and classroom. The sample comprised 64 children (55 males) diagnosed with ASD (mean age = 9.26 years; mean FSIQ = 92). Analyses indicated that parent and teacher ratings of EF (except Shift and Emotional Control) were consistently related to ADHD symptom severity, but not to ASD severity. Thus, functioning in the domains of Shift and Emotional control appear relatively spared, whereas performance in all other EF was impaired in relation to ADHD symptoms., Author(s): Rachel R. Lee [sup.1] , Anthony R. Ward [sup.1] , David M. Lane [sup.2] , Michael G. Aman [sup.3] , Katherine A. Loveland [sup.1] , Rosleen Mansour [sup.1] , [...]

We explore a major European competition decision, the 2012-18 Gazprom case, using a global gas market simulation model. We find that access to LNG markets alone is insufficient to counterbalance Gazprom's strategic behaviour; central and eastern Europe (CEE) needs to be well interconnected with bidirectional flow capability. 'Swap deals' created by the decision facilitate CEE market integration, while limiting Gazprom's potential market power. Such deals may increase the diversity of contracted gas and number of market players, but do not improve physical supply diversity. In the next five years, swap deals could marginally impact negatively the utilization of strategic assets in CEE, but since Gazprom's commitments expire by mid-2026, utilization of these strategic assets may fall considerably, especially if Gazprom withholds supplies. As an unintended consequence, CEE markets may disintegrate from the rest of Europe. Avoiding such outcomes will require further gas market reforms, particularly, market design for gas transportation. Keywords: Gazprom; European Commission, Market Power; Natural Gas; Security of Supply; Competition; Long-term contracts; Swap deals., 1. INTRODUCTION Healthy energy markets hinge on effective competition rules and, critically, on how those rules are implemented. From the early 2000s onwards, the Directorate-General for Competition (DG COMP) of [...]

'I DON'T THINK PARENTS should be telling schools what they should teach,' commented former Virginia governor Terry McAuliffe, a Democrat, while seeking a return to office in 2021. His Republican [...]

THE COVID-19 PANDEMIC PROMPTED the largest disruption to American education in living memory. At the onset of the crisis in spring 2020, nearly every K-12 school, public and private, closed [...]

Coccidioides immitis and C. posadasii, the etiologic agents of coccidioidomycosis, also known as Valley fever, are environmental filamentous fungi with distinct geographic ranges in the western United States, northern Mexico, [...]

: Introduction: HIV pre‐exposure prophylaxis (PrEP) has been recommended and partly subsidized in Québec, Canada, since 2013. We evaluated the population‐level impact of PrEP on HIV transmission among men who have sex with men (MSM) in Montréal, Québec's largest city, over 2013–2021. Methods: We used an agent‐based mathematical model of sexual HIV transmission to estimate the fraction of HIV acquisitions averted by PrEP compared to a counterfactual scenario without PrEP. The model was calibrated to local MSM survey, surveillance, and cohort data and accounted for COVID‐19 pandemic impacts on sexual activity, HIV prevention, and care. PrEP was modelled from 2013 onwards, assuming 86% individual‐level effectiveness. The PrEP eligibility criteria were: any anal sex unprotected by condoms (past 6 months) and either multiple partnerships (past 6 months) or multiple uses of post‐exposure prophylaxis (lifetime). To assess potential optimization strategies, we modelled hypothetical scenarios prioritizing PrEP to MSM with high sexual activity (≥11 anal sex partners annually) or aged ⩽45 years, increasing coverage to levels achieved in Vancouver, Canada (where PrEP is free‐of‐charge), and improving retention. Results: Over 2013–2021, the estimated annual HIV incidence decreased from 0.4 (90% credible interval [CrI]: 0.3–0.6) to 0.2 (90% CrI: 0.1–0.2) per 100 person‐years. PrEP coverage among HIV‐negative MSM remained low until 2015 ( Conclusions: PrEP reduced population‐level HIV transmission among Montréal MSM. However, our study suggests missed prevention opportunities and adds support for public policies that reduce PrEP barriers, financial or otherwise, to MSM at risk of HIV acquisition., INTRODUCTION After over 20 years under study [1–3] and 10 years of availability [4], oral pre‐exposure prophylaxis (PrEP) has proven highly efficacious for preventing HIV acquisition across transmission routes. Rigorous [...]

Herpes zoster (HZ) is a substantial problem for people with decreased cell-mediated immunity, including older adults. The first vaccine approved for HZ prevention, the zoster vaccine live (ZVL), which provided limited and short-lived protection, has been supplanted by the superior recombinant zoster vaccine (RZV), which provides robust and durable protection. To understand the mechanisms underlying the differential immunologic characteristics of the 2 vaccines, we used T cell receptor [beta] chain sequencing and peptide-MHC class II tetramer staining to analyze recombinant glycoprotein E-specific (gE- specific) [CD4.sup.+] T cell clonotypes in RZV and ZVL recipients. Compared with ZVL, RZV expanded more gE-specific [CD4.sup.+] clonotypes, with greater breadth and higher frequency of public clonotypes. RZV recruited a higher proportion of clonotypes from naive than from memory cells, while ZVL recruited equally from memory and naive compartments. Compared with memory-derived, naive-derived clonotypes were more likely to last 5 or more years after immunization. Moreover, the frequency of [tetramer.sup.+] persistent clones correlated with the frequency of [tetramer.sup.+] naive [CD4.sup.+] prevaccination T cells. We conclude that the ability of RZV to recruit naive [CD4.sup.+] T cells into the response may contribute to the durability of its effect. The abundance, breadth, and frequency of public clonotypes may further add to its protective effect., Introduction Herpes zoster (HZ) is a severe disease caused by reactivation of varicella-zoster virus (VZV) that is not optimally controlled by the immune system. Protection against HZ is primarily mediated [...]

Background: Mechanisms for how environmental chemicals might influence pain has received little attention. Epidemiological studies suggest that environmental factors such as pollutants might play a role in migraine prevalence. Potential targets for pollutants are the transient receptor potential (TRP) channels ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1), which on activation release pain-inducing neuropeptide calcitonin generelated peptide (CGRP). Objective: In this study, we aimed to examine the hypothesis that environmental pollutants via TRP channel signaling and subsequent CGRP release trigger migraine signaling and pain. Methods: A calcium imaging-based screen of environmental chemicals was used to investigate activation of migraine pain- associated TRP channels TRPA1 and TRPV1. Based on this screen, whole-cell patch clamp and in silico docking were performed for the pesticide pentachlorophenol (PCP) as proof of concept. Subsequently, PCP-mediated release of CGRP and vasodilatory responses of cerebral arteries were investigated. Finally, we tested whether PCP could induce a TRPA1-dependent induction of cutaneous hypersensitivity in vivo in mice as a model of migraine-like pain. Results: A total of 16 out of the 52 screened environmental chemicals activated TRPA1 at 10 or 100 [micro]M. None of the investigated compounds activated TRPV1. Using PCP as a model of chemical interaction with TRPA1, in silico molecular modeling suggested that PCP is stabilized in a lipidbinding pocket of TRPA1 in comparison with TRPV1. In vitro, ex vivo, and in vivo experiments showed that PCP induced calcium influx in neurons and resulted in a TRPA1-dependent CGRP release from the brainstem and dilation of cerebral arteries. In a mouse model of migraine-like pain, PCP induced a TRPA1-dependent increased pain response ([N.sub.total] = 144). Discussion: Here we show that multiple environmental pollutants interact with the TRPA1-CGRP migraine pain pathway. The data provide valuable insights into how environmental chemicals can interact with neurobiology and provide a potential mechanism for putative increases in migraine prevalence over the last decades. https://doi.org/10.1289/EHP12413, Introduction In 2016, the World Health Organization (WHO) found migraine to be the second largest cause of disability worldwide only exceeded by low back pain. (1) It is debated whether [...]

Clinical genome editing is emerging for rare disease treatment, but one of the major limitations is the targeting of CRISPR editors' delivery. We delivered base editors to the retinal pigmented epithelium (RPE) in the mouse eye using silica nanocapsules (SNCs) as a treatment for retinal degeneration. Leber congenital amaurosis type 16 (LCA16) is a rare pediatric blindness caused by point mutations in the KCNJ13 gene, a loss of function inwardly rectifying potassium channel (Kir7.1) in the RPE. SNCs carrying adenine base editor 8e (ABE8e) mRNA and sgRNA precisely and efficiently corrected the [KCNJ13.sup.W53X/W53X] mutation. Editing in both patient fibroblasts (47%) and human induced pluripotent stem cell-derived RPE (LCA16-iPSC-RPE) (17%) showed minimal off-target editing. We detected functional Kir7.1 channels in the edited LCA16-iPSC-RPE. In the LCA16 mouse model ([Kcnj13.sup.W53X/+[DELTA]R]), RPE cells targeted SNC delivery of ABE8e mRNA preserved normal vision, measured by full-field electroretinogram (ERG). Moreover, multifocal ERG confirmed the topographic measure of electrical activity primarily originating from the edited retinal area at the injection site. Preserved retina structure after treatment was established by optical coherence tomography (OCT). This preclinical validation of targeted ion channel functional rescue, a challenge for pharmacological and genomic interventions, reinforced the effectiveness of nonviral genome-editing therapy for rare inherited disorders., Introduction Leber congenital amaurosis type 16 (LCA16; OMIM #614186) is a severe autosomal recessive inherited retinal dystrophy (IRD) leading to blindness in early life. LCA16 is caused by the loss [...]